金属硫蛋白在抑制糖尿病心肌病中内质网应激介导的心肌细胞凋亡中作用的研究
|
摘要
糖尿病心肌病(DCM)是导致糖尿病患者死亡的主要原因,糖尿病早期就可出现心肌细胞凋亡,凋亡在DCM的发病中占有重要地位,内质网应激(ERS)介导心肌细胞凋亡引起DCM成为研究的热点。金属硫蛋白(MT)是细胞内一组低分子量、富含半胱氨酸的金属结合蛋白,其异构体MT-Ⅰ和MT-Ⅱ主要存在于人类和动物的心脏等器官内。MT是一种有效的、非特异性的抗氧化分子,其在心脏中的功能主要是抗氧化作用。
本研究拟探讨糖尿病、血管紧张素Ⅱ(Ang II)能否诱导ERS及心肌细胞凋亡,以及MT能否抑制糖尿病、Ang II、内质网应激诱导剂-衣霉素诱导的心肌ERS及ERS介导的心肌细胞凋亡。
我们使用STZ在野生型及MT转基因型小鼠中构建1型糖尿病模型。在造模成功后2周、2月及5月,使用免疫印迹法检测ERS信号通路及凋亡标志物,使用TUNEL染色检测凋亡心肌细胞数。凋亡心肌细胞数、CHOP、具有活性的cleaved caspase-3及caspase-12等凋亡标志物在造模成功后2周野生型小鼠心肌中明显升高,而在MT转基因型小鼠中未见改变。与凋亡检测结果平行,ERS标志物GRP78、GRP94、具有活性的cleaved ATF6及p-eIF2α蛋白在野生型小鼠心肌中亦有显著上调,而在MT转基因型小鼠中未见改变。Ang II及衣霉素处理的野生型小鼠中Ang II诱导心肌ERS及细胞凋亡,而在MT转基因型小鼠中未见改变。使用抗氧化剂MnTMPyP或NAC预处理野生型H9c2及MT-ⅡA转基因型H9c2MT7大鼠心肌细胞可以完全抑制Ang II诱导的ERS及ERS介导的心肌细胞凋亡。
本研究证明糖尿病、Ang II诱导心肌ERS及心肌细胞凋亡,MT抑制糖尿病、Ang II、衣霉素诱导的心肌ERS及心肌细胞凋亡,MT通过抗氧化作用抑制Ang II诱导的心肌ERS及心肌细胞凋亡。本研究率先证明在糖尿病心肌中存在ERS,且ERS介导心肌细胞凋亡。本研究率先提出MT能抑制糖尿病及Ang II诱导的ERS及ERS介导的心肌细胞凋亡,其保护机制为通过其抗氧化作用预防DCM。
本研究将为认识DCM发生发展机制及开发治疗糖尿病心血管并发症药物提供理论依据。
DCM is a chronic and complex pathogenesis that is caused by abnormal cellular metabolism and defects in organelles such as myofibrils, mitochondria, and sarcolemma. Apoptotic cell death as an early cellular event in response to diabetes has been reported to play a critical role in DCM development. Although emerging evidence has indicated that ER stress-mediated apoptosis is involved in the pathogenesis of diabetic eye and kidney as well as non-diabetic heart failure, there was no direct evidence for the involvement of ER stress in diabetes-induced cardiac cell death and DCM. Metallothionein (MT) as a potent antioxidant was found to protect the heart from type 1 and type 2 diabetes. In terms of the cellular mechanisms involved in the prevention of MT against DCM, we found that MT protected the heart from diabetes mainly through inhibition of diabetic cardiac cell death. However, it is unclear how diabetes can induce cardiac cell death. The aim of this study was to investigate whether ER stress involves in the development of DCM with streptozotocin (STZ)-induced diabetic models using cardiac-specific MT-overexpression transgenic (MT-TG) mice and their wild-type (WT) mice.The present study shows an association of diabetes- and Ang II-induced cardiac cell death with cardiac ER stress, and also MT prevention of cardiac ER stress and associated cell death in diabetic, Ang II-treated, and chemical ER stressor-treated mouse models.
Methods:
1. Diabetic mouse model: STZ was dissolved in sodium citrate buffer (pH 4.5), and given intraperitoneally to both WT and MT-TG ten-week-old mice at 40 mg/kg body weight daily for 5 days, i.e.multiple low-dose STZ (MLD-STZ) model. Five days after last injection of STZ, whole blood glucose obtained from mouse tail-vein was detected using a SureStep complete blood glucose monitor. STZ-treated mice with whole blood glucose higher than 12 mmol/l were considered diabetic. Animals were sacrificed at 2 week (wk), and 2 and 5 months after the onset of diabetes.
2. Ang II mouse model: Ang II was freshly prepared in a 154 mmol NaCl vehicle immediately prior to be used. MT-TG and WT mice received a single subcutaneous injection of Ang II at 1 mg/kg body weight. Control animals were given an equal volume of vehicle. Both control and Ang II-treated animals were sacrificed at 7 and 24 h later.
3. Tunicamycin mouse model: Both MT-TG and WT mice were intraperitoneally given a single injection of chemical ER stress activator, tunicamycin at 1.5 mg/kg body weight. The tunicamycin was freshly prepared as a 0.05 mg/ml suspension in 150 mM dextrose. Twelve h after tunicamycin treatment, animals were sacrificed.
4. Western blotting assay: Cardiac tissue homogenates were lysed and fractionated electrophoretically on sodium dodecyl (lauryl) sulfate polyacrylamide gel electrophoresis (10%-15% gradient gels), and proteins were transferred to a nitrocellulose membrane. The membrane was blocked with a 5% non-fat, dried milk for 1 h. The following antibodies were used: anti-ATF6 (1:2000,), anti-GRP78 (1:4000), anti-GRP94 (1:1000), anti-p-eIF2αand anti-CHOP (1:200 and 1:500, respectively), anti-cleaved caspase 3 (1:2000), and anti-cleaved caspase 12 (1:1000). Membranes were incubated with the primary antibodies overnight at 4°C. After the unbound antibodies were removed with Tris-buffered saline (pH 7.2) containing 0.05% Tween 20, membranes were incubated with the secondary antibody for 1 h at room temperature. Antigen-antibody complexes were visualized with ECL system.
5. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay: Heart tissue was fixed in 10% formalin, embedded in paraffin, and sectioned at 3-4μm. The slides were stained for TUNEL with the ApopTag Peroxidase In Situ Apoptosis Detection Kit. Each slide was deparaffinized and rehydrated, and treated with proteinase K (20 mg/L) for 15 min. The endogenous peroxidase was inhibited with 3% hydrogen peroxide for 5 min and then incubated with the TUNEL reaction mixture containing terminal deoxynucleotidyl transferase (TdT) and digoxigenin-11-dUTP for 1 h at 37°C. The TdT reaction was carried out in a humidified chamber at 37°C for 1 h, and then 3, 3-diaminobenzidine (DAB) chromogen was applied. Methyl green was used as counterstaining. Mouse testicular tissue was used as positive control. For negative control, TdT was omitted from the reaction mixture. The apoptotic cell death was quantitatively analyzed by counting the TUNEL-positive cells randomly selected from 5 fields from each of the 3 slides for each mouse.
6. Cell culture: Embryonic rat heart derived cells (H9c2) were maintained in DMEM supplemented with 10% fetal bovine serum (FBS) and antibiotics (50 U/ml penicillin and 50μg/ml streptomycin) at 37°C in an atmosphere of 95% air and 5% CO2. Both H9c2 and H9c2MT7 cells were treated with Ang II at 100 nM for 24 h. In some experiments, H9c2 cells were pre-treated with MnTMPyP, a cell-permeable superoxide dismutase mimic, at 50μM for 30 min or NAC, an antioxidant N-acetyl-L-cysteine at 100μM for 24 h and then exposed to Ang II at 100 nM with the presence of either MnTMPyP or NAC for 24 h.
Results:
1. Diabetes-induced cardiac ER stress and prevention by MT
Western blotting assay showed that both phosphorylated eIF2α(p-eIF2α) and GRP94 proteins were significantly increased in the heart of WT diabetic mice at 2 wk, but not 2 and 5 months, after diabetes onset . Cleaved ATF6 protein was significantly increased both at 2 wk and 2 months, but not at 5 month. In contrast to the above changes, GRP78 protein level was increased in the heart of diabetic mice at all three time-points with the highest expression at 2 wk after diabetes . More importantly, none of these increased ER chaperones in the hearts of WT diabetic mice were observed in the heart of MT-TG diabetic mice.
2. Diabetes-induced cardiac MT up-regulation
Western blotting assay revealed that diabetes induced a significant increase in MT contents of heart from 2 wk to 5 months with a rapid increase at 2 wk and then gradually decrease until 5 months after diabetes, but it remains significantly higher than control levels. Interestingly, diabetes-induced cardiac MT synthesis in the heart of WT mice was not observed in the heart of MT-TG diabetic mice.
3. Diabetes-induced cardiac cell death and prevention by MT
we examine the cardiac cell death from 2 wk to 2 and 5 months after diabetes onset with TUNEL assay for apoptotic cells and Western blotting assay for CHOP, the activated form of caspase-3 and caspase-12. Both assays delineate that diabetes mainly induced cardiac cell death at the early stage of diabetes (2 wk), but not in the late stages (2 and 5 months). However, there was no apoptotic cell death in the hearts of MT-TG diabetic mice.
4. Ang II-induced cardiac ER stress and prevention by MT
Treatment of mice with Ang II significantly increased the expression of p-eIF2α, cleaved ATF6 and GRP78 except for GRP94. The up-regulated ER chaperone proteins by Ang II were not observed in the heart of MT-TG mice.
5. Ang II-induced cardiac MT up-regulation
Ang II significantly induced cardiac MT synthesis only in the WT mice, as observed in the hearts of diabetic mice.
6. Ang II -induced cardiac cell death and prevention by MT
Ang II significantly induced cardiac cell death only in the WT mice, as observed in the hearts of diabetic mice. The association of Ang II-induced cardiac cell death with ER stress was also favored by significant increases in CHOP protein expression and caspase-12 activation.
7. Tunicamycin-induced cardiac ER stress and prevention by MT
Western blotting assay showed that proteins of p-eIF2α, cleaved ATF6 and GRP78 all were significantly up-regulated, except for GRP94 protein that was not changed. Similar to the above experiments in diabetic and Ang II-infusion models, MT significantly prevented tunicamycin-up-regulated ER chaperone proteins.
8. Tunicamycin-induced cardiac MT up-regulation
It is noted that tunicamycin also significantly induced cardiac MT synthesis, as shown in the hearts of other ER-stress models.
9. Tunicamycin-induced cardiac cell death and prevention by MT
Cardiac cell death was significantly increased in the heart of Tu-treated WT mice, but not Tu-treated MT-TG mice, examined by Western blotting for caspase-3 activation and TUNEL assay, and confirmed by the increased CHOP protein expression and caspase-12 cleavage.
10. Ang II-induced ER stress was attenuated by MT in cultured cardiac cells
Treatment with Ang II at 100 nM for 24 h significantly induced ER stress, shown by increased expressions of cleaved ATF6, p-eIF2α, GRP78 and GRP94. All these ER-stress effects were not observed in H9c2MT7 cells, suggesting the protection of cardiac cells by MT from Ang II-induced ER stress.
11. Ang II-induced cell death was attenuated by MT in cultured cardiac cells
Treatment with Ang II at 100 nM for 24 h also significantly induced apoptotic cell death in H9c2 cells, measured by CHOP protein expression and caspase-12 activation, but not in H9c2MT7 cells. This in vitro finding is consistent with those of in vivo study.
12. antioxidants-induced ER stress was attenuated by MT in cultured cardiac cells
Pre-exposure of H9c2 cells to MnTMPyP at 50μM for 30 min or NAC at 50μM for 24 h significantly prevented Ang II-induced ER stress, while same pretreatments did not have any effect on normal H9c2 cells and H9c2MT7 cells.
13. antioxidants-induced cell death was attenuated by MT in cultured cardiac cells
Pre-exposure of H9c2 cells to MnTMPyP at 50μM for 30 min or NAC at 50μM for 24 h significantly prevented Ang II-induced apoptosis, while same pretreatments did not have any effect on normal H9c2 cells and H9c2MT7 cells.
Conclusion:
1. We successfully set up streptozotocin (STZ)-induced diabetic, Ang II and tunicamycin- induced mice models, using cardiac-specific MT-overexpression transgenic (MT-TG) mice and their wild-type (WT) mice.
2. Cardiac cell death mediated by ER stress is one of the nosogenesis of DCM;
3. MT can attenuate diabetes-induced cardiac cell death via suppression of cardiac ER stress;
4. Oxidative stress plays a pivotal role in Ang II-induced both ER stress and associated apoptotic effects;
5. Prevention of Ang II-induced ER stress and associated apoptotic effects by MT is most likely mediated by its antioxidant action.
Innovative findings:
1. Diabetes induces cardiac ER stress along with induction of cardiac cell death;
2. MT can attenuate diabetes-, Ang II- and chemical ER stressor-induced cardiac cell death via suppression of cardiac ER stress;
3. MT can protect DCM by suppression of endoplasmic reticulum stress.
本研究拟探讨糖尿病、血管紧张素Ⅱ(Ang II)能否诱导ERS及心肌细胞凋亡,以及MT能否抑制糖尿病、Ang II、内质网应激诱导剂-衣霉素诱导的心肌ERS及ERS介导的心肌细胞凋亡。
我们使用STZ在野生型及MT转基因型小鼠中构建1型糖尿病模型。在造模成功后2周、2月及5月,使用免疫印迹法检测ERS信号通路及凋亡标志物,使用TUNEL染色检测凋亡心肌细胞数。凋亡心肌细胞数、CHOP、具有活性的cleaved caspase-3及caspase-12等凋亡标志物在造模成功后2周野生型小鼠心肌中明显升高,而在MT转基因型小鼠中未见改变。与凋亡检测结果平行,ERS标志物GRP78、GRP94、具有活性的cleaved ATF6及p-eIF2α蛋白在野生型小鼠心肌中亦有显著上调,而在MT转基因型小鼠中未见改变。Ang II及衣霉素处理的野生型小鼠中Ang II诱导心肌ERS及细胞凋亡,而在MT转基因型小鼠中未见改变。使用抗氧化剂MnTMPyP或NAC预处理野生型H9c2及MT-ⅡA转基因型H9c2MT7大鼠心肌细胞可以完全抑制Ang II诱导的ERS及ERS介导的心肌细胞凋亡。
本研究证明糖尿病、Ang II诱导心肌ERS及心肌细胞凋亡,MT抑制糖尿病、Ang II、衣霉素诱导的心肌ERS及心肌细胞凋亡,MT通过抗氧化作用抑制Ang II诱导的心肌ERS及心肌细胞凋亡。本研究率先证明在糖尿病心肌中存在ERS,且ERS介导心肌细胞凋亡。本研究率先提出MT能抑制糖尿病及Ang II诱导的ERS及ERS介导的心肌细胞凋亡,其保护机制为通过其抗氧化作用预防DCM。
本研究将为认识DCM发生发展机制及开发治疗糖尿病心血管并发症药物提供理论依据。
DCM is a chronic and complex pathogenesis that is caused by abnormal cellular metabolism and defects in organelles such as myofibrils, mitochondria, and sarcolemma. Apoptotic cell death as an early cellular event in response to diabetes has been reported to play a critical role in DCM development. Although emerging evidence has indicated that ER stress-mediated apoptosis is involved in the pathogenesis of diabetic eye and kidney as well as non-diabetic heart failure, there was no direct evidence for the involvement of ER stress in diabetes-induced cardiac cell death and DCM. Metallothionein (MT) as a potent antioxidant was found to protect the heart from type 1 and type 2 diabetes. In terms of the cellular mechanisms involved in the prevention of MT against DCM, we found that MT protected the heart from diabetes mainly through inhibition of diabetic cardiac cell death. However, it is unclear how diabetes can induce cardiac cell death. The aim of this study was to investigate whether ER stress involves in the development of DCM with streptozotocin (STZ)-induced diabetic models using cardiac-specific MT-overexpression transgenic (MT-TG) mice and their wild-type (WT) mice.The present study shows an association of diabetes- and Ang II-induced cardiac cell death with cardiac ER stress, and also MT prevention of cardiac ER stress and associated cell death in diabetic, Ang II-treated, and chemical ER stressor-treated mouse models.
Methods:
1. Diabetic mouse model: STZ was dissolved in sodium citrate buffer (pH 4.5), and given intraperitoneally to both WT and MT-TG ten-week-old mice at 40 mg/kg body weight daily for 5 days, i.e.multiple low-dose STZ (MLD-STZ) model. Five days after last injection of STZ, whole blood glucose obtained from mouse tail-vein was detected using a SureStep complete blood glucose monitor. STZ-treated mice with whole blood glucose higher than 12 mmol/l were considered diabetic. Animals were sacrificed at 2 week (wk), and 2 and 5 months after the onset of diabetes.
2. Ang II mouse model: Ang II was freshly prepared in a 154 mmol NaCl vehicle immediately prior to be used. MT-TG and WT mice received a single subcutaneous injection of Ang II at 1 mg/kg body weight. Control animals were given an equal volume of vehicle. Both control and Ang II-treated animals were sacrificed at 7 and 24 h later.
3. Tunicamycin mouse model: Both MT-TG and WT mice were intraperitoneally given a single injection of chemical ER stress activator, tunicamycin at 1.5 mg/kg body weight. The tunicamycin was freshly prepared as a 0.05 mg/ml suspension in 150 mM dextrose. Twelve h after tunicamycin treatment, animals were sacrificed.
4. Western blotting assay: Cardiac tissue homogenates were lysed and fractionated electrophoretically on sodium dodecyl (lauryl) sulfate polyacrylamide gel electrophoresis (10%-15% gradient gels), and proteins were transferred to a nitrocellulose membrane. The membrane was blocked with a 5% non-fat, dried milk for 1 h. The following antibodies were used: anti-ATF6 (1:2000,), anti-GRP78 (1:4000), anti-GRP94 (1:1000), anti-p-eIF2αand anti-CHOP (1:200 and 1:500, respectively), anti-cleaved caspase 3 (1:2000), and anti-cleaved caspase 12 (1:1000). Membranes were incubated with the primary antibodies overnight at 4°C. After the unbound antibodies were removed with Tris-buffered saline (pH 7.2) containing 0.05% Tween 20, membranes were incubated with the secondary antibody for 1 h at room temperature. Antigen-antibody complexes were visualized with ECL system.
5. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay: Heart tissue was fixed in 10% formalin, embedded in paraffin, and sectioned at 3-4μm. The slides were stained for TUNEL with the ApopTag Peroxidase In Situ Apoptosis Detection Kit. Each slide was deparaffinized and rehydrated, and treated with proteinase K (20 mg/L) for 15 min. The endogenous peroxidase was inhibited with 3% hydrogen peroxide for 5 min and then incubated with the TUNEL reaction mixture containing terminal deoxynucleotidyl transferase (TdT) and digoxigenin-11-dUTP for 1 h at 37°C. The TdT reaction was carried out in a humidified chamber at 37°C for 1 h, and then 3, 3-diaminobenzidine (DAB) chromogen was applied. Methyl green was used as counterstaining. Mouse testicular tissue was used as positive control. For negative control, TdT was omitted from the reaction mixture. The apoptotic cell death was quantitatively analyzed by counting the TUNEL-positive cells randomly selected from 5 fields from each of the 3 slides for each mouse.
6. Cell culture: Embryonic rat heart derived cells (H9c2) were maintained in DMEM supplemented with 10% fetal bovine serum (FBS) and antibiotics (50 U/ml penicillin and 50μg/ml streptomycin) at 37°C in an atmosphere of 95% air and 5% CO2. Both H9c2 and H9c2MT7 cells were treated with Ang II at 100 nM for 24 h. In some experiments, H9c2 cells were pre-treated with MnTMPyP, a cell-permeable superoxide dismutase mimic, at 50μM for 30 min or NAC, an antioxidant N-acetyl-L-cysteine at 100μM for 24 h and then exposed to Ang II at 100 nM with the presence of either MnTMPyP or NAC for 24 h.
Results:
1. Diabetes-induced cardiac ER stress and prevention by MT
Western blotting assay showed that both phosphorylated eIF2α(p-eIF2α) and GRP94 proteins were significantly increased in the heart of WT diabetic mice at 2 wk, but not 2 and 5 months, after diabetes onset . Cleaved ATF6 protein was significantly increased both at 2 wk and 2 months, but not at 5 month. In contrast to the above changes, GRP78 protein level was increased in the heart of diabetic mice at all three time-points with the highest expression at 2 wk after diabetes . More importantly, none of these increased ER chaperones in the hearts of WT diabetic mice were observed in the heart of MT-TG diabetic mice.
2. Diabetes-induced cardiac MT up-regulation
Western blotting assay revealed that diabetes induced a significant increase in MT contents of heart from 2 wk to 5 months with a rapid increase at 2 wk and then gradually decrease until 5 months after diabetes, but it remains significantly higher than control levels. Interestingly, diabetes-induced cardiac MT synthesis in the heart of WT mice was not observed in the heart of MT-TG diabetic mice.
3. Diabetes-induced cardiac cell death and prevention by MT
we examine the cardiac cell death from 2 wk to 2 and 5 months after diabetes onset with TUNEL assay for apoptotic cells and Western blotting assay for CHOP, the activated form of caspase-3 and caspase-12. Both assays delineate that diabetes mainly induced cardiac cell death at the early stage of diabetes (2 wk), but not in the late stages (2 and 5 months). However, there was no apoptotic cell death in the hearts of MT-TG diabetic mice.
4. Ang II-induced cardiac ER stress and prevention by MT
Treatment of mice with Ang II significantly increased the expression of p-eIF2α, cleaved ATF6 and GRP78 except for GRP94. The up-regulated ER chaperone proteins by Ang II were not observed in the heart of MT-TG mice.
5. Ang II-induced cardiac MT up-regulation
Ang II significantly induced cardiac MT synthesis only in the WT mice, as observed in the hearts of diabetic mice.
6. Ang II -induced cardiac cell death and prevention by MT
Ang II significantly induced cardiac cell death only in the WT mice, as observed in the hearts of diabetic mice. The association of Ang II-induced cardiac cell death with ER stress was also favored by significant increases in CHOP protein expression and caspase-12 activation.
7. Tunicamycin-induced cardiac ER stress and prevention by MT
Western blotting assay showed that proteins of p-eIF2α, cleaved ATF6 and GRP78 all were significantly up-regulated, except for GRP94 protein that was not changed. Similar to the above experiments in diabetic and Ang II-infusion models, MT significantly prevented tunicamycin-up-regulated ER chaperone proteins.
8. Tunicamycin-induced cardiac MT up-regulation
It is noted that tunicamycin also significantly induced cardiac MT synthesis, as shown in the hearts of other ER-stress models.
9. Tunicamycin-induced cardiac cell death and prevention by MT
Cardiac cell death was significantly increased in the heart of Tu-treated WT mice, but not Tu-treated MT-TG mice, examined by Western blotting for caspase-3 activation and TUNEL assay, and confirmed by the increased CHOP protein expression and caspase-12 cleavage.
10. Ang II-induced ER stress was attenuated by MT in cultured cardiac cells
Treatment with Ang II at 100 nM for 24 h significantly induced ER stress, shown by increased expressions of cleaved ATF6, p-eIF2α, GRP78 and GRP94. All these ER-stress effects were not observed in H9c2MT7 cells, suggesting the protection of cardiac cells by MT from Ang II-induced ER stress.
11. Ang II-induced cell death was attenuated by MT in cultured cardiac cells
Treatment with Ang II at 100 nM for 24 h also significantly induced apoptotic cell death in H9c2 cells, measured by CHOP protein expression and caspase-12 activation, but not in H9c2MT7 cells. This in vitro finding is consistent with those of in vivo study.
12. antioxidants-induced ER stress was attenuated by MT in cultured cardiac cells
Pre-exposure of H9c2 cells to MnTMPyP at 50μM for 30 min or NAC at 50μM for 24 h significantly prevented Ang II-induced ER stress, while same pretreatments did not have any effect on normal H9c2 cells and H9c2MT7 cells.
13. antioxidants-induced cell death was attenuated by MT in cultured cardiac cells
Pre-exposure of H9c2 cells to MnTMPyP at 50μM for 30 min or NAC at 50μM for 24 h significantly prevented Ang II-induced apoptosis, while same pretreatments did not have any effect on normal H9c2 cells and H9c2MT7 cells.
Conclusion:
1. We successfully set up streptozotocin (STZ)-induced diabetic, Ang II and tunicamycin- induced mice models, using cardiac-specific MT-overexpression transgenic (MT-TG) mice and their wild-type (WT) mice.
2. Cardiac cell death mediated by ER stress is one of the nosogenesis of DCM;
3. MT can attenuate diabetes-induced cardiac cell death via suppression of cardiac ER stress;
4. Oxidative stress plays a pivotal role in Ang II-induced both ER stress and associated apoptotic effects;
5. Prevention of Ang II-induced ER stress and associated apoptotic effects by MT is most likely mediated by its antioxidant action.
Innovative findings:
1. Diabetes induces cardiac ER stress along with induction of cardiac cell death;
2. MT can attenuate diabetes-, Ang II- and chemical ER stressor-induced cardiac cell death via suppression of cardiac ER stress;
3. MT can protect DCM by suppression of endoplasmic reticulum stress.
引文
[1] Roglic G, Unwin N. Mortality attributable to diabetes: estimates for the year 2010[J]. Diabetes Res Clin Pract;87(1):15-9.
[2] Rubler S, Dlugash J, Yuceoglu YZ, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis[J]. Am J Cardiol 1972;30(6):595-602.
[3] Hamby RI, Zoneraich S, Sherman L, et al. Diabetic cardiomyopathy[J]. Jama 1974;229 (13):1749-54.
[4] Kannel WB, Hjortland M, Castelli WP, et al. Role of diabetes in congestive heart failure: the Framingham study[J]. Am J Cardiol 1974;34(1):29-34.
[5] Cai L, Li W, Wang G, et al. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway[J]. Diabetes 2002;51(6):1938-48.
[6] Katare RG, Caporali A, Oikawa A, et al. Vitamin B1 analog benfotiamine prevents diabetes-induced diastolic dysfunction and heart failure through Akt/Pim-1-mediated survival pathway[J]. Circ Heart Fail 2010; 3(2):294-305.
[7] Basu R, Oudit GY, Wang X, et al. Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function Am J Physiol Heart[J]. Circ Physiol 2009; 297(6): H2096 - H2108.
[8] Codinach Huix P, Freixa Pamias R. Diabetic cardiomyopathy: concept, heart function, and pathogenesis[J]. An Med Interna 2002;19(6):313-20.
[9] Boudina S, Abel ED. Diabetic cardiomyopathy revisited[J]. Circulation2007; 115(25):3213-23.
[10] An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy[J]. Am J Physiol Heart Circ Physiol 2006;291(4):H1489-506.
[11] Maya L, Villarreal FJ. Diagnostic approaches for diabetic cardiomyopathy andmyocardial fibrosis[J]. J Mol Cell Cardiol 2010;48(3):524-9.
[12] Aneja A,Tang WH, Bansilal S, et al. Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options[J]. Am J Med 2008 Sep;121(9):748-57.
[13] Coort SL, Bonen A, van der Vusse GJ, et al. Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: role of sarcolemmal substrate transporters[J].Mol Cell Biochem 2007;299(1-2):5-18.
[14] Schwenk RW, Luiken JJ, Bonen A, et al. Regulation of sarcolemmal glucose and fatty acid transporters in cardiac disease[J]. Cardiovasc Res 2008;79(2):249-58.
[15] Rodrigues B, Cam MC, McNeill JH. Metabolic disturbances in diabetic cardiomyopathy[J]. Mol Cell Biochem 1998;180(1-2):53-7.
[16] Ren J, Davidoff AJ. Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes[J]. Am J Physiol 1997;272(1 Pt 2):H148-58.
[17] Davidoff AJ, Ren J. Low insulin and high glucose induce abnormal relaxation in cultured adult rat ventricular myocytes[J]. Am J Physiol 1997;272(1 Pt 2):H159-67.
[18] Garvey WT, Hardin D, Juhaszova M, Dominguez JH. Effects of diabetes on myocardial glucose transport system in rats: implications for diabetic cardiomyopathy[J]. Am J Physiol 1993;264(3 Pt 2):H837-44.
[19] Guertl B, Noehammer C, Hoefler G. Metabolic cardiomyopathies[J]. Int J Exp Pathol 2000;81(6):349-72.
[20] Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress[J]. Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78.
[21] Geraldes P,King GL. Activation of protein kinase C isoforms and its impact on diabetic complications[J]. Circ Res 2010;106(8):1319-31.
[22] He Z, Way KJ, Arikawa E, et al. Differential regulation of angiotensin II-induced expression of connective tissue growth factor by protein kinase C isoforms in the myocardium[J]. J Biol Chem 2005;280(16):15719-26.
[23] Tsao TS, Burcelin R, Charron MJ. Regulation of hexokinase II gene expression by glucose flux in skeletal muscle[J]. J Biol Chem 1996;271(25):14959-63.
[24] Liu Q, Docherty JC, Rendell JC, et al. High levels of fatty acids delay the recoveryof intracellular pH and cardiac efficiency inpost-ischemic hearts by inhibiting glucose oxidation[J]. J Am Coll Cardiol2002;39(4):718-25.
[25] Forcheron F, Basset A, Abdallah P, et al. Diabetic cardiomyopathy: effects of fenofibrate and metformin in an experimental model--the Zucker diabetic rat[J]. Cardiovasc Diabetol 2009;8:16.
[26] Kennedy AL, Lyons TJ. Glycation, oxidation, and lipoxidation in the development of diabetic complications[J]. Metabolism 1997;46(12 Suppl 1):14-21.
[27] Shepherd G, Cam MC, Sambandam N, et al. Streptozotocin-induced diabetes enhances cardiac heparin-releasable lipoprotein lipase activity in spontaneously hypertensive rats[J]. Hypertension 1998;31(3):878-84.
[28] Sambandam N, Abrahani MA, Craig S, et al. Metabolism of VLDL is increased in streptozotocin-induced diabetic rat hearts[J]. Am J Physiol Heart Circ Physiol 2000;278(6):H1874-82.
[29] Dyntar D, Eppenberger-Eberhardt M, Maedler K, et al. Glucose and palmitic acid induce degeneration of myofibrils and modulate apoptosis in rat adult cardiomyocytes[J]. Diabetes 2001;50(9):2105-13.
[30] Wang J, Song Y, Wang Q, et al. Causes and characteristics of diabetic cardiomyopathy[J]. Rev Diabet Stud 2006;3(3):108-17.
[31] Kusminski CM, Shetty S, Orci L, et al. Diabetes and apoptosis: lipotoxicity[J]. Apoptosis2009;14(12):1484-95.
[32] Nakayama H, Morozumi T, Nanto S, et al. Abnormal myocardial free fatty acid utilization deteriorates with morphological changes in the hypertensive heart[J]. Jpn Circ J 2001;65(9):783-7.
[33] Unger RH, Orci L. Diseases of liporegulation: new perspective on obesity andrelated disorders[J]. Faseb J 2001;15(2):312-21.
[34] Finck BN. The role of the peroxisome proliferator-activated receptor alpha pathway in pathological remodeling of the diabetic heart[J]. Curr Opin Clin Nutr Metab Care 2004;7(4):391-6.
[35] Schiffrin EL. Peroxisome proliferator-activated receptors and cardiovascular remodeling[J]. Am J Physiol Heart Circ Physiol 2005;288(3):H1037-43.
[36] Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy: a brief review[J]. Cardiovasc Toxicol 2001;1(3):181-93.
[37] Brownlee M. Biochemistry and molecular cell biology of diabetic complications[J]. Nature 2001;414(6865):813-20.
[38] Rosen P, Nawroth PP, King G, et al. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society[J]. Diabetes Metab Res Rev 2001;17(3):189-212.
[39] Monkemann H, De Vriese AS, Blom HJ, et al. Early molecular events in the development of the diabetic cardiomyopathy[J]. Amino Acids 2002;23(1-3):331-6.
[40] Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus[J]. J Clin Invest 2002;109(1):121-30.
[41] Christoffersen C, Bollano E, Lindegaard ML, et al. Cardiac lipid accumulation associated with diastolic dysfunction in obese mice[J]. Endocrinology 2003;144(8):3483-90.
[42] Santos DL, Palmeira CM, Seica R, et al. Diabetes and mitochondrial oxidative stress: a study using heart mitochondria from the diabetic Goto-Kakizaki rat[J]. Mol Cell Biochem 2003;246(1-2):163-70.
[43] Ceriello A. Nitrotyrosine: new findings as a marker of postprandial oxidative stress[J]. Int J Clin Pract Suppl 2002(129):51-8.
[44] Ohkuwa T, Sato Y, Naoi M. Hydroxyl radical formation in diabetic rats induced bystreptozotocin[J]. Life Sci 1995;56(21):1789-98.
[45] Pennathur S, Wagner JD, Leeuwenburgh C, et al. A hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease[J]. J Clin Invest 2001;107(7):853-60.
[46] Fiordaliso F, Li B, Latini R, et al. Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent[J]. Lab Invest 2000;80(4):513-27.
[47] Zou MH, Shi C, Cohen RA. High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/ prostaglandin H(2) receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells[J]. Diabetes 2002;51(1):198-203.
[48] Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite[J]. J Clin Invest 2002;109 (6):817-26.
[49] Frustaci A, Kajstura J, Chimenti C, et al. Myocardial cell death in human diabetes[J]. Circ Res 2000;87(12):1123-32.
[50] Matsui H, Okumura K, Mukawa H, et al. Increased oxysterol contents in diabetic rat hearts: their involvement in diabetic cardiomyopathy[J]. Can J Cardiol 1997;13(4):373-9.
[51] Tomita M, Mukae S, Geshi E, et al. Mitochondrial respiratory impairment in streptozotocin-induced diabetic rat heart[J]. Jpn Circ J 1996;60(9):673-82.
[52] Kucharska J, Braunova Z, Ulicna O, et al. Deficit of coenzyme Q in heart and liver mitochondria of rats with streptozotocin-induced diabetes[J]. Physiol Res 2000;49(4):411-8.
[53] Koufen P, Ruck A, Brdiczka D, et al. Free radical-induced inactivation of creatine kinase: influence on the octameric and dimeric states of the mitochondrial enzyme (Mib-CK) [J]. Biochem J 1999;344 Pt 2:413-7.
[54] Kaneko M, Matsumoto Y, Hayashi H, Kobayashi A, et al. Oxygen free radicals and calcium homeostasis in the heart[J]. Mol Cell Biochem 1994;139(1):91-100.
[55] Kakkar R, Kalra J, Mantha SV, et al. Lipid peroxidation and activity of antioxidant enzymes in diabetic rats[J]. Mol Cell Biochem 1995;151(2):113-9.
[56] Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts[J]. Am J Physiol Cell Physiol 2001;280(1):C53-60.
[57] Uemura S, Matsushita H, Li W, et al. Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress[J]. Circ Res 2001;88(12):1291-8.
[58] Monnier VM, Glomb M, Elgawish A, et al. The mechanism of collagen cross-linking in diabetes: a puzzle nearing resolution[J]. Diabetes 1996;45 Suppl 3:S67-72.
[59] Yamagishi SI, Edelstein D, Du XL, et al. Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction[J]. Diabetes 2001;50(6):1491-4.
[60] Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin[J]. J Clin Invest 1980;65(1):128-35.
[61] Chen Y, Saari JT, Kang YJ. Weak antioxidant defenses make the heart a target for damage in copper-deficient rats[J]. Free Radic Biol Med 1994;17(6):529-36.
[62] Kersten JR, Schmeling TJ, Orth KG, et al. Acute hyperglycemia abolishes ischemic preconditioning in vivo[J]. Am J Physiol 1998;275(2 Pt 2):H721-5.
[63] Joyeux M, Faure P, Godin-Ribuot D, et al. Heat stress fails to protect myocardium of streptozotocin-induced diabetic rats against infarction[J]. Cardiovasc Res 1999;43(4):939-46.
[64] Elangovan V, Shohami E, Gati I, Kohen R. Increased hepatic lipid soluble antioxidant capacity as compared to other organs of streptozotocin-induced diabetic rats: a cyclic voltammetry study[J]. Free Radic Res 2000;32(2):125-34.
[65] Kajstura J, Fiordaliso F, Andreoli AM, et al. IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress[J]. Diabetes 2001;50(6):1414-24.
[66] Listenberger LL, Ory DS, Schaffer JE. Palmitate-induced apoptosis can occurthrough a ceramide-independent pathway[J]. J Biol Chem 2001;276(18):14890-5.
[67] Susic D, Varagic J, Ahn J, et al. Collagen cross-link breakers: a beginning of a new era in the treatment of cardiovascular changes associated with aging, diabetes, and hypertension[J]. Curr Drug Targets Cardiovasc Haematol Disord 2004;4(1):97- 101.
[68] Goldin A, Beckman JA, Schmidt AM, et al. Advanced glycation end products: sparking the development of diabetic vascular injury[J]. Circulation 2006;114(6):597- 605.
[69] Bierhaus A, Chevion S, Chevion M, et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha- lipoic acid in cultured endothelial cells[J]. Diabetes 1997;46(9):1481-90.
[70] Dostal DE, Rothblum KN, Chernin MI, et al. Intracardiac detection of angiotensinogen and renin: a localized renin-angiotensin system in neonatal rat heart[J]. Am J Physiol 1992;263(4 Pt 1):C838-50.
[71] Weber KT, Sun Y, Tyagi SC, et al. Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms[J]. J Mol Cell Cardiol 1994;26(3):279-92.
[72] Gibbons GH, Pratt RE, Dzau VJ. Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II[J]. J Clin Invest 1992;90(2):456-61.
[73] Zhou G, Li X, Hein DW, et al. Metallothionein suppresses angiotensin II-induced nicotinamide adenine dinucleotide phosphate oxidase activation, nitrosative stress, apoptosis, and pathological remodeling in the diabetic heart[J]. J Am Coll Cardiol 2008;52(8):655-66.
[74] Ren J, Bode AM. Altered cardiac excitation-contraction coupling in ventricular myocytes from spontaneously diabetic BB rats[J]. Am J Physiol Heart Circ Physiol 2000;279(1):H238-44.
[75] Ren J, Gintant GA, Miller RE, et al. High extracellular glucose impairs cardiac E-C coupling in a glycosylation-dependent manner[J]. Am J Physiol 1997;273(6 Pt 2):H2876-83.
[76] O'Connor B. Diabetes and cardiovascular disease[J]. Adv Exp Med Biol 2001;498:367-71.
[77] Hattori Y, Matsuda N, Kimura J, et al. Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: implication in Ca2+ overload[J]. J Physiol 2000;527 Pt 1:85-94.
[78] Zhao XY, Hu SJ, Li J, et al. Decreased cardiac sarcoplasmic reticulum Ca2+ -ATPase activity contributes to cardiac dysfunction in streptozotocin-induced diabetic rats[J]. J Physiol Biochem 2006;62(1):1-8.
[79] Chattou S, Diacono J, Feuvray D. Decrease in sodium-calcium exchange and calcium currents in diabetic rat ventricular myocytes[J]. Acta Physiol Scand 1999;166(2):137-44.
[80] Wang DW, Kiyosue T, Shigematsu S, et al. Abnormalities of K+ and Ca2+ currents in ventricular myocytes from rats with chronic diabetes[J]. Am J Physiol 1995;269(4 Pt 2):H1288-96.
[81] Shimoni Y, Firek L, Severson D, et al. Short-term diabetes alters K+ currents in rat ventricular myocytes[J]. Circ Res 1994;74(4):620-8.
[82] Mizushige K, Yao L, Noma T, et al. Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model[J]. Circulation 2000;101(8):899-907.
[83] Asbun J, Villarreal FJ. The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy[J]. J Am Coll Cardiol 2006;47(4):693-700.
[84] Sivasubramanian N, Coker ML, Kurrelmeyer KM, et al. Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor[J]. Circulation 2001;104(7):826-31.
[85] Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications[J]. Endocr Rev 2004;25(4):543-67.
[86] Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic[J]. Nature 2001;414(6865):782-7.
[87] Trost S, LeWinter M. Diabetic Cardiomyopathy[J]. Curr Treat Options CardiovascMed 2001;3(6):481-92.
[88] Giles TD. The patient with diabetes mellitus and heart failure: at-risk issues[J]. Am J Med 2003;115 Suppl 8A:107S-10S.
[89] Cai L, Kang YJ. Cell death and diabetic cardiomyopathy[J]. Cardiovasc Toxicol 2003;3(3):219-28.
[90] Dyntar D, Sergeev P, Klisic J, et al. High glucose alters cardiomyocyte contacts and inhibits myofibrillar formation[J]. J Clin Endocrinol Metab 2006;91(5):1961-7.
[91] Ghosh S, Rodrigues B. Cardiac cell death in early diabetes and its modulation by dietary fatty acids[J]. Biochim Biophys Acta 2006;1761(10):1148-62.
[92] Harmancey R, Taegtmeyer H. The complexities of diabetic cardiomyopathy: lessons from patients and animal models[J]. Curr Diab Rep 2008;8(3):243-8.
[93] Hayat SA, Patel B, Khattar RS, et al. Diabetic cardiomyopathy: mechanisms, diagnosis and treatment[J]. Clin Sci (Lond) 2004;107(6):539-57.
[94] Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways[J]. Nat Cell Biol 2001;3(11):E255-63.
[95] Haynes CM, Titus EA, Cooper AA. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death[J]. Mol Cell 2004;15(5):767-76.
[96] Momoi T. Caspases involved in ER stress-mediated cell death[J]. J Chem Neuroanat 2004;28(1-2):101-5.
[97] Sakaki K, Kaufman RJ. Regulation of ER stress-induced macroautophagy by protein kinase C[J]. Autophagy 2008;4(6):841-3.
[98] Sakaki K, Wu J, Kaufman RJ. Protein kinase Ctheta is required for autophagy in response to stress in the endoplasmic reticulum[J]. J Biol Chem 2008;283(22):15370-80.
[99] Shi Y, Vattem KM, Sood R, et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control[J]. Mol Cell Biol 1998;18(12):7499-509.
[100] Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by anendoplasmic-reticulum-resident kinase[J]. Nature 1999;397(6716):271-4.
[101] Bertolotti A, Zhang Y, Hendershot LM, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response[J]. Nat Cell Biol 2000;2(6):326-32.
[102] Ma K, Vattem KM, Wek RC. Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress[J]. J Biol Chem 2002;277(21):18728-35.
[103] Ma Y, Hendershot LM. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress[J]. J Biol Chem 2003;278 (37):34864-73.
[104] Thoma C, Bergamini G, Galy B, et al. Enhancement of IRES-mediated translation of the c-myc and BiP mRNAs by the poly(A) tail is independent of intact eIF4G and PABP[J]. Mol Cell 2004;15(6):925-35.
[105] Harding HP, Novoa I, Zhang Y, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells[J]. Mol Cell 2000;6(5):1099-108.
[106] Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response[J]. J Cell Biol 2004;167(1):27-33.
[107] Zinszner H, Kuroda M, Wang X, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum[J]. Genes Dev 1998;12(7):982-95.
[108] McCullough KD, Martindale JL, Klotz LO, et al. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state[J]. Mol Cell Biol 2001;21(4):1249-59.
[109] Adler HT, Chinery R, Wu DY, et al. Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins[J]. Mol Cell Biol 1999;19(10):7050-60.
[110] Du K, Herzig S, Kulkarni RN, et al. TRB3: a tribbles homolog that inhibitsAkt/PKB activation by insulin in liver[J]. Science 2003;300(5625):1574-7.
[111] Marciniak SJ, Yun CY, Oyadomari S, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum[J]. Genes Dev 2004;18(24):3066-77.
[112] Yoneda T, Imaizumi K, Oono K, et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress[J]. J Biol Chem 2001;276(17):13935-40.
[113] Nishitoh H, Matsuzawa A, Tobiume K, et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats[J]. Genes Dev 2002;16(11):1345-55.
[114] Cox JS, Shamu CE, Walter P. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase[J]. Cell 1993;73(6):1197-206.
[115] Mori K, Ma W, Gething MJ, et al. A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus[J]. Cell 1993;74(4):743-56.
[116] Shamu CE, Walter P. Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus[J]. Embo J 1996;15(12):3028-39.
[117] Kohno K, Normington K, Sambrook J, et al. The promoter region of the yeast KAR2 (BiP) gene contains a regulatory domain that responds to the presence of unfolded proteins in the endoplasmic reticulum[J]. Mol Cell Biol 1993;13(2):877-90.
[118] Sidrauski C, Walter P. The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response[J]. Cell 1997;90(6):1031-9.
[119] Clauss IM, Chu M, Zhao JL, et al. The basic domain/leucine zipper protein hXBP-1 preferentially binds to and transactivates CRE-like sequences containing an ACGT core[J].Nucleic Acids Res 1996;24(10):1855-64.
[120] Hetz C, Bernasconi P, Fisher J, et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha[J]. Science 2006;312(5773):572-6.
[121] Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response[J]. Mol Cell Biol 2003;23(21):7448-59.
[122] Yoshida H, Oku M, Suzuki M, et al. pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response[J]. J Cell Biol 2006;172(4):565-75.
[123] Zhu C, Johansen FE, Prywes R. Interaction of ATF6 and serum response factor[J]. Mol Cell Biol 1997;17(9):4957-66.
[124] Yoshida H, Haze K, Yanagi H, et al. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors[J]. J Biol Chem 1998;273(50):33741-9.
[125] Shen J, Snapp EL, Lippincott-Schwartz J, et al. Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response[J]. Mol Cell Biol 2005;25(3):921-32.
[126] Nadanaka S, Okada T, Yoshida H, et al. Role of disulfide bridges formed in the luminal domain of ATF6 in sensing endoplasmic reticulum stress[J]. Mol Cell Biol 2007;27(3):1027-43.
[127] Shen J, Chen X, Hendershot L, et al. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals[J]. Dev Cell 2002;3(1):99-111.
[128] Ye J, Rawson RB, Komuro R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs[J]. Mol Cell 2000;6(6):1355-64.
[129] Thuerauf DJ, Arnold ND, Zechner D, et al. p38 Mitogen-activated protein kinase mediates the transcriptional induction of the atrial natriuretic factor gene through a serum response element. A potential role for the transcription factor ATF6[J]. J Biol Chem 1998;273(32):20636-43.
[130] Haze K, Yoshida H, Yanagi H, et al. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress[J]. Mol Biol Cell 1999;10(11):3787-99.
[131] Wang Y, Shen J, Arenzana N, et al. Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response[J]. J Biol Chem 2000;275(35):27013-20.
[132] Yoshida H, Okada T, Haze K, et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response[J]. Mol Cell Biol 2000;20(18):6755- 67.
[133] Li M, Baumeister P, Roy B, et al. ATF6 as a transcription activator of the endoplasmic reticulum stress element: thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1[J]. Mol Cell Biol 2000;20(14):5096-106.
[134] Yoshida H, Okada T, Haze K, et al. Endoplasmic reticulum stress-induced formation of transcription factor complex ERSF including NF-Y (CBF) and activating transcription factors 6alpha and 6beta that activates the mammalian unfolded protein response[J]. Mol Cell Biol 2001;21(4):1239-48.
[135] Kokame K, Kato H, Miyata T. Identification of ERSE-II, a new cis-acting element responsible for the ATF6-dependent mammalian unfolded protein response[J]. J Biol Chem 2001;276(12):9199-205.
[136] Parker R, Phan T, Baumeister P, et al. Identification of TFII-I as the endoplasmic reticulum stress response element binding factor ERSF: its autoregulation by stress and interaction with ATF6[J]. Mol Cell Biol 2001;21 (9):3220-33.
[137] Ma Y, Hendershot LM. Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with othercellular stress pathways[J]. J Biol Chem 2004;279(14):13792-9.
[138] Zeng L, Lu M, Mori K, et al. ATF6 modulates SREBP2- mediated lipogenesis[J]. Embo J 2004;23(4):950-8.
[139] Glembotski CC. Endoplasmic reticulum stress in the heart[J]. Circ Res 2007;101(10):975-84.
[140] Yamamoto K, Yoshida H, Kokame K, et al. Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II[J]. J Biochem 2004;136(3):343-50.
[141] Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions[J]. J Clin Invest 2005;115(10):2656-64.
[142] Sundar Rajan S, Srinivasan V, Balasubramanyam M, et al. Endoplasmic reticulum (ER) stress & diabetes[J]. Indian J Med Res 2007;125(3):411-24.
[143] Cai L. Alcoholic cardiomyopathy: acetaldehyde, insulin insensitization and ER stress[J]. J Mol Cell Cardiol 2008;44(6):979-82.
[144] Hettiarachchi KD, Zimmet PZ, Myers MA. Dietary Toxins, Endoplasmic Reticulum (ER) Stress and Diabetes[J]. Curr Diabetes Rev 2008;4(2):146-56.
[145] Kaneto H, Matsuoka TA, Nakatani Y, et al. Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes[J]. J Mol Med 2005;83(6):429-39.
[146] Yoshida H. ER stress and diseases[J]. Febs J 2007;274(3):630-58.
[147] Li SY, Ren J. Cardiac overexpression of alcohol dehydrogenase exacerbates chronic ethanol ingestion-induced myocardial dysfunction and hypertrophy: role of insulin signaling and ER stress[J]. J Mol Cell Cardiol 2008;44(6):992-1001.
[148] Liu J, Mao W, Iwai C, et al. Adoptive passive transfer of rabbit beta1-adrenoceptor peptide immune cardiomyopathy into the Rag2-/- mouse: participation of the ER stress[J]. J Mol Cell Cardiol 2008;44(2):304-14.
[149] Mao W, Iwai C, Liu J, et al. Darbepoetin alfa exerts a cardioprotective effect in autoimmune cardiomyopathy via reduction of ER stress and activation of the PI3K/Akt andSTAT3 pathways[J]. J Mol Cell Cardiol 2008;45(2):250-60.
[150] Szegezdi E, Duffy A, O'Mahoney ME, et al. ER stress contributes to ischemia-induced cardiomyocyte apoptosis[J]. Biochem Biophys Res Commun 2006;349(4):1406-11.
[151] Bhimji S, Godin DV, McNeill JH. Myocardial ultrastructural changes in alloxan-induced diabetes in rabbits[J]. Acta Anat (Basel) 1986;125(3):195-200.
[152] Jackson CV, McGrath GM, Tahiliani AG, et al. A functional and ultrastructural analysis of experimental diabetic rat myocardium[J]. Manifestation of a cardiomyopathy. Diabetes 1985;34(9):876-83.
[153] Okada K, Minamino T, Tsukamoto Y, et al. Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis[J]. Circulation 2004;110(6):705-12
[154] Nakatani Y, Kaneto H, Kawamori D, et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes[J]. J Biol Chem 2005;280(1):847-51.
[155] Ma Y, Brewer JW, Diehl JA, et al. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response[J]. J Mol Biol 2002;318(5):1351-65.
[156] Wang XZ, Lawson B, Brewer JW, et al. Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153)[J]. Mol Cell Biol 1996;16(8):4273-80.
[157] Harding HP, Zhang Y, Zeng H, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress[J]. Mol Cell 2003;11(3):619-33.
[158] Pahl HL, Baeuerle PA. The ER-overload response: activation of NF-kappa B[J]. Trends Biochem Sci 1997;22(2):63-7.
[159] Hotamisligil GS. Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes[J]. Diabetes 2005;54Suppl 2:S73-8.
[160] Hetz C, Russelakis-Carneiro M, Maundrell K, et al. Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein[J]. Embo J 2003;22(20):5435-45.
[161] Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta[J]. Nature 2000;403(6765):98-103.
[162] Morishima N, Nakanishi K, Takenouchi H, et al. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12[J]. J Biol Chem 2002;277(37):34287-94.
[163] Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death[J]. Cell Death Differ 2006;13(3):363-73.
[164] Zhang K, Kaufman RJ. The unfolded protein response: a stress signaling pathway critical for health and disease[J]. Neurology 2006;66(2 Suppl 1):S102-9.
[165] Buytaert E, Callewaert G, Hendrickx N, et al. Role of endoplasmic reticulum depletion and multidomain proapoptotic BAX and BAK proteins in shaping cell death after hypericin-mediated photodynamic therapy[J]. Faseb J 2006;20(6):756-8.
[166] MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial[J]. Lancet 2002;360 (9326):23-33.
[167] Vega-Lopez S, Devaraj S, Jialal I. Oxidative stress and antioxidant supplementation in the management of diabetic cardiovascular disease[J]. J Investig Med 2004;52(1):24-32.
[168] Wiernsperger NF. Oxidative stress as a therapeutic target in diabetes: revisiting the controversy[J]. Diabetes Metab 2003;29(6):579-85.
[169] Cowell RM, Russell JW. Nitrosative injury and antioxidant therapy in the management of diabetic neuropathy[J]. J Investig Med 2004;52(1):33-44.
[170] Kang YJ. The antioxidant function of metallothionein in the heart[J]. Proc Soc ExpBiol Med 1999;222(3):263-73.
[171] Ceriello A. New insights on oxidative stress and diabetic complications may lead to a "causal" antioxidant therapy[J]. Diabetes Care 2003;26(5):1589-96.
[172] Cai L, Satoh M, Tohyama C, et al. Metallothionein in radiation exposure: its induction and protective role[J]. Toxicology 1999;132(2-3):85-98.
[173] Nath R, Kumar D, Li T, et al. Metallothioneins, oxidative stress and the cardiovascular system[J]. Toxicology 2000;155(1-3):17-26.
[174] Cai L, Cherian MG. Zinc-metallothionein protects from DNA damage induced by radiation better than glutathione and copper- or cadmium-metallothioneins[J]. Toxicol Lett 2003;136(3):193-8.
[175] Hamer DH. Metallothionein[J]. Annu Rev Biochem 1986;55:913-51.
[176] Vasak M. Advances in metallothionein structure and functions[J]. J Trace Elem Med Biol 2005;19(1):13-7.
[177] Rigby Duncan KE, Stillman MJ. Metal-dependent protein folding: metallation of metallothionein[J]. J Inorg Biochem 2006;100(12):2101-7.
[178] Marcellini M, Di Ciommo V, Callea F, et al. Treatment of Wilson's disease with zinc from the time of diagnosis in pediatric patients: a single-hospital, 10-year follow-up study[J]. J Lab Clin Med 2005;145(3):139-43.
[179] Hoogenraad TU. Paradigm shift in treatment of Wilson's disease: zinc therapy now treatment of choice[J]. Brain Dev 2006;28(3):141-6.
[180] Gonzalez BP, Nino Fong R, Gibson CJ, et al. Zinc supplementation decreases hepatic copper accumulation in LEC rat: a model of Wilson's disease[J]. Biol Trace Elem Res 2005;105(1-3):117-34.
[181] Krezel A, Maret W. Different redox states of metallothionein/thionein in biological tissue[J]. Biochem J 2007;402(3):551-8.
[182] Stitt MS, Wasserloos KJ, Tang X, et al. Nitric oxide-induced nuclear translocation of the metal responsive transcription factor, MTF-1 is mediated by zinc release frommetallothionein[J]. Vascul Pharmacol 2006;44(3):149-55.
[183] Casero E, Martin-Gago JA, Pariente F, et al Metal release in metallothioneins induced by nitric oxide: X-ray absorption spectroscopy study[J]. Eur Biophys J 2004;33(8):726-31.
[184] Quesada AR, Byrnes RW, Krezoski SO, et al. Direct reaction of H2O2 with sulfhydryl groups in HL-60 cells: zinc-metallothionein and other sites[J]. Arch Biochem Biophys 1996;334(2):241-50.
[185] Miura T, Muraoka S, Ogiso T. Antioxidant activity of metallothionein compared with reduced glutathione[J]. Life Sci 1997;60(21):PL 301-9.
[186] Cai L, Klein JB, Kang YJ. Metallothionein inhibits peroxynitrite-induced DNA and lipoprotein damage[J]. J Biol Chem 2000;275(50):38957-60.
[187] Thornalley PJ, Vasak M. Possible role for metallothionein in protection against radiation-induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals[J]. Biochim Biophys Acta 1985;827(1):36-44.
[188] Abel J, de Ruiter N. Inhibition of hydroxyl-radical-generated DNA degradation by metallothionein[J]. Toxicol Lett 1989;47(2):191-6.
[189] Sharma SK, Ebadi M. Metallothionein attenuates 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in dopaminergic neurons[J]. Antioxid Redox Signal 2003;5(3):251-64.
[190] Li X, Chen H, Epstein PN. Metallothionein protects islets from hypoxia and extends islet graft survival by scavenging most kinds of reactive oxygen species[J]. J Biol Chem 2004;279(1):765-71.
[191] Onosaka S, Cherian MG. The induced synthesis of metallothionein in various tissues of rat in response to metals. I. Effect of repeated injection of cadmium salts[J]. Toxicology 1981;22(2):91-101.
[192] Bauman JW, Liu J, Liu YP, et al. Increase in metallothionein produced by chemicals that induce oxidative stress[J]. Toxicol Appl Pharmacol 1991;110(2):347-54.
[193] Kang YJ, Chen Y, Yu A, et al. Overexpression of metallothionein in the heart of transgenic mice suppresses doxorubicin cardiotoxicity[J]. J Clin Invest 1997;100(6):1501-6.
[194] Zhou Z, Kang YJ. Immunocytochemical localization of metallothionein and its relation to doxorubicin toxicity in transgenic mouse heart[J]. Am J Pathol 2000;156(5):1653-62.
[195] Kang YJ, Zhou ZX, Wu H, et al. Metallothionein inhibits myocardial apoptosis in copper-deficient mice: role of atrial natriuretic peptide[J]. Lab Invest 2000;80(5):745-57.
[196] Kang YJ, Li Y, Sun X, et al. Antiapoptotic effect and inhibition of ischemia/reperfusion-induced myocardial injury in metallothionein-overexpressing transgenic mice[J]. Am J Pathol 2003;163(4):1579-86.
[197] Feng W, Benz FW, Cai J, et al. Metallothionein disulfides are present in metallothionein-overexpressing transgenic mouse heart and increase under conditions of oxidative stress[J]. J Biol Chem 2006;281(2):681-7.
[198] Cai L, Wang J, Li Y, et al. Inhibition of superoxide generation and associated nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy[J]. Diabetes 2005;54(6):1829-37.
[199] Cai L, Wang Y, Zhou G, et al. Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy[J]. J Am Coll Cardiol 2006;48(8):1688-97.
[200] Song Y, Wang J, Li Y, et al. Cardiac metallothionein synthesis in streptozotocin-induced diabetic mice, and its protection against diabetes-induced cardiac injury[J]. Am J Pathol 2005;167(1):17-26.
[201] Wang J, Song Y, Elsherif L, et al. Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation[J]. Circulation 2006;113(4):544-54.
[202] Feng W, Wang Y, Cai L, et al. Metallothionein rescues hypoxia-inducible factor-1 transcriptional activity in cardiomyocytes under diabetic conditions[J]. Biochem Biophys ResCommun 2007;360(1):286-9.
[203] Cai L. Suppression of nitrative damage by metallothionein in diabetic heart contributes to the prevention of cardiomyopathy[J]. Free Radic Biol Med 2006;41(6):851-61.
[204] Cai L. Diabetic cardiomyopathy and its prevention by metallothionein: experimental evidence, possible mechanisms and clinical implications[J]. Curr Med Chem 2007;14(20):2193-203.
[205] Szabo C, Mabley JG, Moeller SM, et al. Part I: pathogenetic role of peroxynitrite in the development of diabetes and diabetic vascular complications: studies with FP15, a novel potent peroxynitrite decomposition catalyst[J]. Mol Med 2002;8(10):571-80.
[206] Failla ML, Kiser RA. Altered tissue content and cytosol distribution of trace metals in experimental diabetes[J]. J Nutr 1981;111(11):1900-9.
[207] Failla ML, Kiser RA. Hepatic and renal metabolism of copper and zinc in the diabetic rat[J]. Am J Physiol 1983;244(2):E115-21.
[208] Chen ML, Failla ML. Metallothionein metabolism in the liver and kidney of the streptozotocin-diabetic rat[J]. Comp Biochem Physiol B 1988;90(2):439-45.
[209] Failla ML, Gardell CY. Influence of spontaneous diabetes on tissue status of zinc, copper, and manganese in the BB Wistar rat[J]. Proc Soc Exp Biol Med 1985;180(2):317-22.
[210] Kennedy ML, Failla ML. Zinc metabolism in genetically obese (ob/ob) mice[J]. J Nutr 1987;117(5):886-93.
[211] Apostolova MD, Chen S, Chakrabarti S, et al. High-glucose-induced metallothionein expression in endothelial cells: an endothelin-mediated mechanism[J]. Am J Physiol Cell Physiol 2001;281(3):C899-907.
[212] Meugnier E, Faraj M, Rome S, et al. Acute hyperglycemia induces a global downregulation of gene expression in adipose tissue and skeletal muscle of healthy subjects[J]. Diabetes 2007;56(4):992-9.
[213] Beltramini M, Zambenedetti P, Raso M, et al. The effect of Zn(II) and streptozotocin administration in the mouse brain[J]. Brain Res 2006;1109(1):207-18.
[214] Lecker SH, Jagoe RT, Gilbert A, et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression[J]. Faseb J 2004;18(1):39-51.
[215] Gerhardinger C, Costa MB, Coulombe MC, et al. Expression of acute-phase response proteins in retinal Muller cells in diabetes[J]. Invest Ophthalmol Vis Sci 2005;46(1):349-57.
[216] Puskas LG, Nagy ZB, Giricz Z, et al. Cholesterol diet-induced hyperlipidemia influences gene expression pattern of rat hearts: a DNA microarray study[J]. FEBS Lett 2004;562(1-3):99-104.
[217] Uriu-Adams JY, Rucker RB, Commisso JF, et al. Diabetes and dietary copper alter 67Cu metabolism and oxidant defense in the rat[J]. J Nutr Biochem 2005;16(5):312-20.
[218] Liang Q, Carlson EC, Donthi RV, et al. Overexpression of metallothionein reduces diabetic cardiomyopathy[J]. Diabetes 2002;51 (1):174-81.
[219] Ceylan-Isik AF, LaCour KH, Ren J. Sex difference in cardiomyocyte function in normal and metallothionein transgenic mice: the effect of diabetes mellitus[J]. J Appl Physiol 2006;100(5):1638-46.
[220] Fang CX, Dong F, Ren BH, et al. Metallothionein alleviates cardiac contractile dysfunction induced by insulin resistance: role of Akt phosphorylation, PTB1B, PPARgamma and c-Jun[J]. Diabetologia 2005;48(11):2412-21.
[221] Ye G, Metreveli NS, Donthi RV, et al. Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes[J]. Diabetes 2004;53(5):1336-43.
[222] Shen X, Zheng S, Metreveli NS, et al. Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy[J]. Diabetes 2006;55(3):798- 805.
[223] Privratsky JR, Wold LE, Sowers JR, et al. AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase[J]. Hypertension 2003;42(2):206-12.
[224] Ye G, Metreveli NS, Ren J, et al. Metallothionein prevents diabetes- induceddeficits in cardiomyocytes by inhibiting reactive oxygen species production[J]. Diabetes 2003;52(3):777-83.
[225] Wold LE, Ceylan-Isik AF, Fang CX, et al. Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme[J]. Free Radic Biol Med 2006;40(8):1419-29.
[226] Trost SU, Belke DD, Bluhm WF, et al. Overexpression of the sarcoplasmic reticulum Ca(2+)-ATPase improves myocardial contractility in diabetic cardiomyopathy[J]. Diabetes 2002;51(4):1166-71.
[227] Maier LS, Wahl-Schott C, Horn W, et al. Increased SR Ca2+ cycling contributes to improved contractile performance in SERCA2a-overexpressing transgenic rats[J]. Cardiovasc Res 2005;67(4):636-46.
[228] Kralik PM, Ye G, Metreveli NS, et al. Cardiomyocyte dysfunction in models of type 1 and type 2 diabetes[J]. Cardiovasc Toxicol 2005;5(3):285-92.
[229] Ayaz M, Turan B. Selenium prevents diabetes-induced alterations in [Zn2+]i and metallothionein level of rat heart via restoration of cell redox cycle[J]. Am J Physiol Heart Circ Physiol 2006;290(3):H1071-80.
[230] Korichneva I. Zinc dynamics in the myocardial redox signaling network[J]. Antioxid Redox Signal 2006;8(9-10):1707-21.
[231] Feng W, Cai J, Pierce WM, et al. Metallothionein transfers zinc to mitochondrial aconitase through a direct interaction in mouse hearts[J]. Biochem Biophys Res Commun 2005;332(3):853-8.
[232] Song Y, Wang J, Li XK, et al. Zinc and the diabetic heart[J]. Biometals 2005;18(4):325-32.
[233] Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of the heart in diabetes: Part I: general concepts[J]. Circulation 2002;105(14):1727-33.
[234] DeBosch B, Sambandam N, Weinheimer C, et al. Akt2 regulates cardiacmetabolism and cardiomyocyte survival[J]. J Biol Chem 2006;281 (43):32841-51.
[235] Muslin AJ, DeBosch B. Role of Akt in cardiac growth and metabolism[J]. Novartis Found Symp 2006;274:118-26; discussion 26-31,52-5,272-6.
[236] Miranda ER, Dey CS. Effect of chromium and zinc on insulin signaling in skeletal muscle cells[J]. Biol Trace Elem Res 2004;101(1):19-36.
[237] Simon SF, Taylor CG. Dietary zinc supplementation attenuates hyperglycemia in db/db mice[J]. Exp Biol Med (Maywood) 2001;226(1):43-51.
[238] Canatan H, Bakan I, Akbulut M, et al. Relationship among levels of leptin and zinc, copper, and zinc/copper ratio in plasma of patients with essential hypertension and healthy normotensive subjects[J]. Biol Trace Elem Res 2004;100(2):117-23.
[239] Anetor JI, Senjobi A, Ajose OA, et al. Decreased serum magnesium and zinc levels: atherogenic implications in type-2 diabetes mellitus in Nigerians[J]. Nutr Health 2002;16(4):291-300.
[240] Roussel AM, Kerkeni A, Zouari N, et al. Antioxidant effects of zinc supplementation in Tunisians with type 2 diabetes mellitus[J]. J Am Coll Nutr 2003;22(4):316-21.
[241] Kajanachumpol S, Srisurapanon S, Supanit I, et al. Effect of zinc supplementation on zinc status, copper status and cellular immunity in elderly patients with diabetes mellitus[J]. J Med Assoc Thai 1995;78(7):344-9.
[242] Al-Maroof RA, Al-Sharbatti SS. Serum zinc levels in diabetic patients and effect of zinc supplementation on glycemic control of type 2 diabetics[J]. Saudi Med J 2006;27(3):344-50.
[243] Kadhim HM, Ismail SH, Hussein KI, et al. Effects of melatonin and zinc on lipid profile and renal function in type 2 diabetic patients poorly controlled with metformin[J]. J Pineal Res 2006;41(2):189-93.
[244] Farvid MS, Jalali M, Siassi F, et al. Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes[J]. Diabetes Care 2005;28(10):2458-64.
[245] Faure P, Benhamou PY, Perard A, et al. Lipid peroxidation in insulin-dependent diabetic patients with early retina degenerative lesions: effects of an oral zinc supplementation[J]. Eur J Clin Nutr 1995;49(4):282-8.
[246] Gupta R, Garg VK, Mathur DK, et al. Oral zinc therapy in diabetic neuropathy[J]. J Assoc Physicians India 1998;46(11):939-42.
[247] Hayee MA, Mohammad QD, Haque A. Diabetic neuropathy and zinc therapy[J]. Bangladesh Med Res Counc Bull 2005;31(2):62-7.
[248] Kosar F, Sahin I, Taskapan C, et al. Trace element status (Se, Zn, Cu) in heart failure[J]. Anadolu Kardiyol Derg 2006;6(3):216-20.
[249] Giacconi R, Cipriano C, Muti E, et al. Novel -209A/G MT2A polymorphism in old patients with type 2 diabetes and atherosclerosis: relationship with inflammation (IL-6) and zinc[J]. Biogerontology 2005;6(6):407-13.
[250] Soinio M, Marniemi J, Laakso M, et al. Serum zinc level and coronary heart disease events in patients with type 2 diabetes[J]. Diabetes Care 2007;30(3):523-8.
[2] Rubler S, Dlugash J, Yuceoglu YZ, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis[J]. Am J Cardiol 1972;30(6):595-602.
[3] Hamby RI, Zoneraich S, Sherman L, et al. Diabetic cardiomyopathy[J]. Jama 1974;229 (13):1749-54.
[4] Kannel WB, Hjortland M, Castelli WP, et al. Role of diabetes in congestive heart failure: the Framingham study[J]. Am J Cardiol 1974;34(1):29-34.
[5] Cai L, Li W, Wang G, et al. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway[J]. Diabetes 2002;51(6):1938-48.
[6] Katare RG, Caporali A, Oikawa A, et al. Vitamin B1 analog benfotiamine prevents diabetes-induced diastolic dysfunction and heart failure through Akt/Pim-1-mediated survival pathway[J]. Circ Heart Fail 2010; 3(2):294-305.
[7] Basu R, Oudit GY, Wang X, et al. Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function Am J Physiol Heart[J]. Circ Physiol 2009; 297(6): H2096 - H2108.
[8] Codinach Huix P, Freixa Pamias R. Diabetic cardiomyopathy: concept, heart function, and pathogenesis[J]. An Med Interna 2002;19(6):313-20.
[9] Boudina S, Abel ED. Diabetic cardiomyopathy revisited[J]. Circulation2007; 115(25):3213-23.
[10] An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy[J]. Am J Physiol Heart Circ Physiol 2006;291(4):H1489-506.
[11] Maya L, Villarreal FJ. Diagnostic approaches for diabetic cardiomyopathy andmyocardial fibrosis[J]. J Mol Cell Cardiol 2010;48(3):524-9.
[12] Aneja A,Tang WH, Bansilal S, et al. Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options[J]. Am J Med 2008 Sep;121(9):748-57.
[13] Coort SL, Bonen A, van der Vusse GJ, et al. Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: role of sarcolemmal substrate transporters[J].Mol Cell Biochem 2007;299(1-2):5-18.
[14] Schwenk RW, Luiken JJ, Bonen A, et al. Regulation of sarcolemmal glucose and fatty acid transporters in cardiac disease[J]. Cardiovasc Res 2008;79(2):249-58.
[15] Rodrigues B, Cam MC, McNeill JH. Metabolic disturbances in diabetic cardiomyopathy[J]. Mol Cell Biochem 1998;180(1-2):53-7.
[16] Ren J, Davidoff AJ. Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes[J]. Am J Physiol 1997;272(1 Pt 2):H148-58.
[17] Davidoff AJ, Ren J. Low insulin and high glucose induce abnormal relaxation in cultured adult rat ventricular myocytes[J]. Am J Physiol 1997;272(1 Pt 2):H159-67.
[18] Garvey WT, Hardin D, Juhaszova M, Dominguez JH. Effects of diabetes on myocardial glucose transport system in rats: implications for diabetic cardiomyopathy[J]. Am J Physiol 1993;264(3 Pt 2):H837-44.
[19] Guertl B, Noehammer C, Hoefler G. Metabolic cardiomyopathies[J]. Int J Exp Pathol 2000;81(6):349-72.
[20] Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress[J]. Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78.
[21] Geraldes P,King GL. Activation of protein kinase C isoforms and its impact on diabetic complications[J]. Circ Res 2010;106(8):1319-31.
[22] He Z, Way KJ, Arikawa E, et al. Differential regulation of angiotensin II-induced expression of connective tissue growth factor by protein kinase C isoforms in the myocardium[J]. J Biol Chem 2005;280(16):15719-26.
[23] Tsao TS, Burcelin R, Charron MJ. Regulation of hexokinase II gene expression by glucose flux in skeletal muscle[J]. J Biol Chem 1996;271(25):14959-63.
[24] Liu Q, Docherty JC, Rendell JC, et al. High levels of fatty acids delay the recoveryof intracellular pH and cardiac efficiency inpost-ischemic hearts by inhibiting glucose oxidation[J]. J Am Coll Cardiol2002;39(4):718-25.
[25] Forcheron F, Basset A, Abdallah P, et al. Diabetic cardiomyopathy: effects of fenofibrate and metformin in an experimental model--the Zucker diabetic rat[J]. Cardiovasc Diabetol 2009;8:16.
[26] Kennedy AL, Lyons TJ. Glycation, oxidation, and lipoxidation in the development of diabetic complications[J]. Metabolism 1997;46(12 Suppl 1):14-21.
[27] Shepherd G, Cam MC, Sambandam N, et al. Streptozotocin-induced diabetes enhances cardiac heparin-releasable lipoprotein lipase activity in spontaneously hypertensive rats[J]. Hypertension 1998;31(3):878-84.
[28] Sambandam N, Abrahani MA, Craig S, et al. Metabolism of VLDL is increased in streptozotocin-induced diabetic rat hearts[J]. Am J Physiol Heart Circ Physiol 2000;278(6):H1874-82.
[29] Dyntar D, Eppenberger-Eberhardt M, Maedler K, et al. Glucose and palmitic acid induce degeneration of myofibrils and modulate apoptosis in rat adult cardiomyocytes[J]. Diabetes 2001;50(9):2105-13.
[30] Wang J, Song Y, Wang Q, et al. Causes and characteristics of diabetic cardiomyopathy[J]. Rev Diabet Stud 2006;3(3):108-17.
[31] Kusminski CM, Shetty S, Orci L, et al. Diabetes and apoptosis: lipotoxicity[J]. Apoptosis2009;14(12):1484-95.
[32] Nakayama H, Morozumi T, Nanto S, et al. Abnormal myocardial free fatty acid utilization deteriorates with morphological changes in the hypertensive heart[J]. Jpn Circ J 2001;65(9):783-7.
[33] Unger RH, Orci L. Diseases of liporegulation: new perspective on obesity andrelated disorders[J]. Faseb J 2001;15(2):312-21.
[34] Finck BN. The role of the peroxisome proliferator-activated receptor alpha pathway in pathological remodeling of the diabetic heart[J]. Curr Opin Clin Nutr Metab Care 2004;7(4):391-6.
[35] Schiffrin EL. Peroxisome proliferator-activated receptors and cardiovascular remodeling[J]. Am J Physiol Heart Circ Physiol 2005;288(3):H1037-43.
[36] Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy: a brief review[J]. Cardiovasc Toxicol 2001;1(3):181-93.
[37] Brownlee M. Biochemistry and molecular cell biology of diabetic complications[J]. Nature 2001;414(6865):813-20.
[38] Rosen P, Nawroth PP, King G, et al. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society[J]. Diabetes Metab Res Rev 2001;17(3):189-212.
[39] Monkemann H, De Vriese AS, Blom HJ, et al. Early molecular events in the development of the diabetic cardiomyopathy[J]. Amino Acids 2002;23(1-3):331-6.
[40] Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus[J]. J Clin Invest 2002;109(1):121-30.
[41] Christoffersen C, Bollano E, Lindegaard ML, et al. Cardiac lipid accumulation associated with diastolic dysfunction in obese mice[J]. Endocrinology 2003;144(8):3483-90.
[42] Santos DL, Palmeira CM, Seica R, et al. Diabetes and mitochondrial oxidative stress: a study using heart mitochondria from the diabetic Goto-Kakizaki rat[J]. Mol Cell Biochem 2003;246(1-2):163-70.
[43] Ceriello A. Nitrotyrosine: new findings as a marker of postprandial oxidative stress[J]. Int J Clin Pract Suppl 2002(129):51-8.
[44] Ohkuwa T, Sato Y, Naoi M. Hydroxyl radical formation in diabetic rats induced bystreptozotocin[J]. Life Sci 1995;56(21):1789-98.
[45] Pennathur S, Wagner JD, Leeuwenburgh C, et al. A hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease[J]. J Clin Invest 2001;107(7):853-60.
[46] Fiordaliso F, Li B, Latini R, et al. Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent[J]. Lab Invest 2000;80(4):513-27.
[47] Zou MH, Shi C, Cohen RA. High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/ prostaglandin H(2) receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells[J]. Diabetes 2002;51(1):198-203.
[48] Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite[J]. J Clin Invest 2002;109 (6):817-26.
[49] Frustaci A, Kajstura J, Chimenti C, et al. Myocardial cell death in human diabetes[J]. Circ Res 2000;87(12):1123-32.
[50] Matsui H, Okumura K, Mukawa H, et al. Increased oxysterol contents in diabetic rat hearts: their involvement in diabetic cardiomyopathy[J]. Can J Cardiol 1997;13(4):373-9.
[51] Tomita M, Mukae S, Geshi E, et al. Mitochondrial respiratory impairment in streptozotocin-induced diabetic rat heart[J]. Jpn Circ J 1996;60(9):673-82.
[52] Kucharska J, Braunova Z, Ulicna O, et al. Deficit of coenzyme Q in heart and liver mitochondria of rats with streptozotocin-induced diabetes[J]. Physiol Res 2000;49(4):411-8.
[53] Koufen P, Ruck A, Brdiczka D, et al. Free radical-induced inactivation of creatine kinase: influence on the octameric and dimeric states of the mitochondrial enzyme (Mib-CK) [J]. Biochem J 1999;344 Pt 2:413-7.
[54] Kaneko M, Matsumoto Y, Hayashi H, Kobayashi A, et al. Oxygen free radicals and calcium homeostasis in the heart[J]. Mol Cell Biochem 1994;139(1):91-100.
[55] Kakkar R, Kalra J, Mantha SV, et al. Lipid peroxidation and activity of antioxidant enzymes in diabetic rats[J]. Mol Cell Biochem 1995;151(2):113-9.
[56] Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts[J]. Am J Physiol Cell Physiol 2001;280(1):C53-60.
[57] Uemura S, Matsushita H, Li W, et al. Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress[J]. Circ Res 2001;88(12):1291-8.
[58] Monnier VM, Glomb M, Elgawish A, et al. The mechanism of collagen cross-linking in diabetes: a puzzle nearing resolution[J]. Diabetes 1996;45 Suppl 3:S67-72.
[59] Yamagishi SI, Edelstein D, Du XL, et al. Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction[J]. Diabetes 2001;50(6):1491-4.
[60] Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin[J]. J Clin Invest 1980;65(1):128-35.
[61] Chen Y, Saari JT, Kang YJ. Weak antioxidant defenses make the heart a target for damage in copper-deficient rats[J]. Free Radic Biol Med 1994;17(6):529-36.
[62] Kersten JR, Schmeling TJ, Orth KG, et al. Acute hyperglycemia abolishes ischemic preconditioning in vivo[J]. Am J Physiol 1998;275(2 Pt 2):H721-5.
[63] Joyeux M, Faure P, Godin-Ribuot D, et al. Heat stress fails to protect myocardium of streptozotocin-induced diabetic rats against infarction[J]. Cardiovasc Res 1999;43(4):939-46.
[64] Elangovan V, Shohami E, Gati I, Kohen R. Increased hepatic lipid soluble antioxidant capacity as compared to other organs of streptozotocin-induced diabetic rats: a cyclic voltammetry study[J]. Free Radic Res 2000;32(2):125-34.
[65] Kajstura J, Fiordaliso F, Andreoli AM, et al. IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress[J]. Diabetes 2001;50(6):1414-24.
[66] Listenberger LL, Ory DS, Schaffer JE. Palmitate-induced apoptosis can occurthrough a ceramide-independent pathway[J]. J Biol Chem 2001;276(18):14890-5.
[67] Susic D, Varagic J, Ahn J, et al. Collagen cross-link breakers: a beginning of a new era in the treatment of cardiovascular changes associated with aging, diabetes, and hypertension[J]. Curr Drug Targets Cardiovasc Haematol Disord 2004;4(1):97- 101.
[68] Goldin A, Beckman JA, Schmidt AM, et al. Advanced glycation end products: sparking the development of diabetic vascular injury[J]. Circulation 2006;114(6):597- 605.
[69] Bierhaus A, Chevion S, Chevion M, et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha- lipoic acid in cultured endothelial cells[J]. Diabetes 1997;46(9):1481-90.
[70] Dostal DE, Rothblum KN, Chernin MI, et al. Intracardiac detection of angiotensinogen and renin: a localized renin-angiotensin system in neonatal rat heart[J]. Am J Physiol 1992;263(4 Pt 1):C838-50.
[71] Weber KT, Sun Y, Tyagi SC, et al. Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms[J]. J Mol Cell Cardiol 1994;26(3):279-92.
[72] Gibbons GH, Pratt RE, Dzau VJ. Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II[J]. J Clin Invest 1992;90(2):456-61.
[73] Zhou G, Li X, Hein DW, et al. Metallothionein suppresses angiotensin II-induced nicotinamide adenine dinucleotide phosphate oxidase activation, nitrosative stress, apoptosis, and pathological remodeling in the diabetic heart[J]. J Am Coll Cardiol 2008;52(8):655-66.
[74] Ren J, Bode AM. Altered cardiac excitation-contraction coupling in ventricular myocytes from spontaneously diabetic BB rats[J]. Am J Physiol Heart Circ Physiol 2000;279(1):H238-44.
[75] Ren J, Gintant GA, Miller RE, et al. High extracellular glucose impairs cardiac E-C coupling in a glycosylation-dependent manner[J]. Am J Physiol 1997;273(6 Pt 2):H2876-83.
[76] O'Connor B. Diabetes and cardiovascular disease[J]. Adv Exp Med Biol 2001;498:367-71.
[77] Hattori Y, Matsuda N, Kimura J, et al. Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: implication in Ca2+ overload[J]. J Physiol 2000;527 Pt 1:85-94.
[78] Zhao XY, Hu SJ, Li J, et al. Decreased cardiac sarcoplasmic reticulum Ca2+ -ATPase activity contributes to cardiac dysfunction in streptozotocin-induced diabetic rats[J]. J Physiol Biochem 2006;62(1):1-8.
[79] Chattou S, Diacono J, Feuvray D. Decrease in sodium-calcium exchange and calcium currents in diabetic rat ventricular myocytes[J]. Acta Physiol Scand 1999;166(2):137-44.
[80] Wang DW, Kiyosue T, Shigematsu S, et al. Abnormalities of K+ and Ca2+ currents in ventricular myocytes from rats with chronic diabetes[J]. Am J Physiol 1995;269(4 Pt 2):H1288-96.
[81] Shimoni Y, Firek L, Severson D, et al. Short-term diabetes alters K+ currents in rat ventricular myocytes[J]. Circ Res 1994;74(4):620-8.
[82] Mizushige K, Yao L, Noma T, et al. Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model[J]. Circulation 2000;101(8):899-907.
[83] Asbun J, Villarreal FJ. The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy[J]. J Am Coll Cardiol 2006;47(4):693-700.
[84] Sivasubramanian N, Coker ML, Kurrelmeyer KM, et al. Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor[J]. Circulation 2001;104(7):826-31.
[85] Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications[J]. Endocr Rev 2004;25(4):543-67.
[86] Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic[J]. Nature 2001;414(6865):782-7.
[87] Trost S, LeWinter M. Diabetic Cardiomyopathy[J]. Curr Treat Options CardiovascMed 2001;3(6):481-92.
[88] Giles TD. The patient with diabetes mellitus and heart failure: at-risk issues[J]. Am J Med 2003;115 Suppl 8A:107S-10S.
[89] Cai L, Kang YJ. Cell death and diabetic cardiomyopathy[J]. Cardiovasc Toxicol 2003;3(3):219-28.
[90] Dyntar D, Sergeev P, Klisic J, et al. High glucose alters cardiomyocyte contacts and inhibits myofibrillar formation[J]. J Clin Endocrinol Metab 2006;91(5):1961-7.
[91] Ghosh S, Rodrigues B. Cardiac cell death in early diabetes and its modulation by dietary fatty acids[J]. Biochim Biophys Acta 2006;1761(10):1148-62.
[92] Harmancey R, Taegtmeyer H. The complexities of diabetic cardiomyopathy: lessons from patients and animal models[J]. Curr Diab Rep 2008;8(3):243-8.
[93] Hayat SA, Patel B, Khattar RS, et al. Diabetic cardiomyopathy: mechanisms, diagnosis and treatment[J]. Clin Sci (Lond) 2004;107(6):539-57.
[94] Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways[J]. Nat Cell Biol 2001;3(11):E255-63.
[95] Haynes CM, Titus EA, Cooper AA. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death[J]. Mol Cell 2004;15(5):767-76.
[96] Momoi T. Caspases involved in ER stress-mediated cell death[J]. J Chem Neuroanat 2004;28(1-2):101-5.
[97] Sakaki K, Kaufman RJ. Regulation of ER stress-induced macroautophagy by protein kinase C[J]. Autophagy 2008;4(6):841-3.
[98] Sakaki K, Wu J, Kaufman RJ. Protein kinase Ctheta is required for autophagy in response to stress in the endoplasmic reticulum[J]. J Biol Chem 2008;283(22):15370-80.
[99] Shi Y, Vattem KM, Sood R, et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control[J]. Mol Cell Biol 1998;18(12):7499-509.
[100] Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by anendoplasmic-reticulum-resident kinase[J]. Nature 1999;397(6716):271-4.
[101] Bertolotti A, Zhang Y, Hendershot LM, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response[J]. Nat Cell Biol 2000;2(6):326-32.
[102] Ma K, Vattem KM, Wek RC. Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress[J]. J Biol Chem 2002;277(21):18728-35.
[103] Ma Y, Hendershot LM. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress[J]. J Biol Chem 2003;278 (37):34864-73.
[104] Thoma C, Bergamini G, Galy B, et al. Enhancement of IRES-mediated translation of the c-myc and BiP mRNAs by the poly(A) tail is independent of intact eIF4G and PABP[J]. Mol Cell 2004;15(6):925-35.
[105] Harding HP, Novoa I, Zhang Y, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells[J]. Mol Cell 2000;6(5):1099-108.
[106] Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response[J]. J Cell Biol 2004;167(1):27-33.
[107] Zinszner H, Kuroda M, Wang X, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum[J]. Genes Dev 1998;12(7):982-95.
[108] McCullough KD, Martindale JL, Klotz LO, et al. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state[J]. Mol Cell Biol 2001;21(4):1249-59.
[109] Adler HT, Chinery R, Wu DY, et al. Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins[J]. Mol Cell Biol 1999;19(10):7050-60.
[110] Du K, Herzig S, Kulkarni RN, et al. TRB3: a tribbles homolog that inhibitsAkt/PKB activation by insulin in liver[J]. Science 2003;300(5625):1574-7.
[111] Marciniak SJ, Yun CY, Oyadomari S, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum[J]. Genes Dev 2004;18(24):3066-77.
[112] Yoneda T, Imaizumi K, Oono K, et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress[J]. J Biol Chem 2001;276(17):13935-40.
[113] Nishitoh H, Matsuzawa A, Tobiume K, et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats[J]. Genes Dev 2002;16(11):1345-55.
[114] Cox JS, Shamu CE, Walter P. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase[J]. Cell 1993;73(6):1197-206.
[115] Mori K, Ma W, Gething MJ, et al. A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus[J]. Cell 1993;74(4):743-56.
[116] Shamu CE, Walter P. Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus[J]. Embo J 1996;15(12):3028-39.
[117] Kohno K, Normington K, Sambrook J, et al. The promoter region of the yeast KAR2 (BiP) gene contains a regulatory domain that responds to the presence of unfolded proteins in the endoplasmic reticulum[J]. Mol Cell Biol 1993;13(2):877-90.
[118] Sidrauski C, Walter P. The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response[J]. Cell 1997;90(6):1031-9.
[119] Clauss IM, Chu M, Zhao JL, et al. The basic domain/leucine zipper protein hXBP-1 preferentially binds to and transactivates CRE-like sequences containing an ACGT core[J].Nucleic Acids Res 1996;24(10):1855-64.
[120] Hetz C, Bernasconi P, Fisher J, et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha[J]. Science 2006;312(5773):572-6.
[121] Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response[J]. Mol Cell Biol 2003;23(21):7448-59.
[122] Yoshida H, Oku M, Suzuki M, et al. pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response[J]. J Cell Biol 2006;172(4):565-75.
[123] Zhu C, Johansen FE, Prywes R. Interaction of ATF6 and serum response factor[J]. Mol Cell Biol 1997;17(9):4957-66.
[124] Yoshida H, Haze K, Yanagi H, et al. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors[J]. J Biol Chem 1998;273(50):33741-9.
[125] Shen J, Snapp EL, Lippincott-Schwartz J, et al. Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response[J]. Mol Cell Biol 2005;25(3):921-32.
[126] Nadanaka S, Okada T, Yoshida H, et al. Role of disulfide bridges formed in the luminal domain of ATF6 in sensing endoplasmic reticulum stress[J]. Mol Cell Biol 2007;27(3):1027-43.
[127] Shen J, Chen X, Hendershot L, et al. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals[J]. Dev Cell 2002;3(1):99-111.
[128] Ye J, Rawson RB, Komuro R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs[J]. Mol Cell 2000;6(6):1355-64.
[129] Thuerauf DJ, Arnold ND, Zechner D, et al. p38 Mitogen-activated protein kinase mediates the transcriptional induction of the atrial natriuretic factor gene through a serum response element. A potential role for the transcription factor ATF6[J]. J Biol Chem 1998;273(32):20636-43.
[130] Haze K, Yoshida H, Yanagi H, et al. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress[J]. Mol Biol Cell 1999;10(11):3787-99.
[131] Wang Y, Shen J, Arenzana N, et al. Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response[J]. J Biol Chem 2000;275(35):27013-20.
[132] Yoshida H, Okada T, Haze K, et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response[J]. Mol Cell Biol 2000;20(18):6755- 67.
[133] Li M, Baumeister P, Roy B, et al. ATF6 as a transcription activator of the endoplasmic reticulum stress element: thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1[J]. Mol Cell Biol 2000;20(14):5096-106.
[134] Yoshida H, Okada T, Haze K, et al. Endoplasmic reticulum stress-induced formation of transcription factor complex ERSF including NF-Y (CBF) and activating transcription factors 6alpha and 6beta that activates the mammalian unfolded protein response[J]. Mol Cell Biol 2001;21(4):1239-48.
[135] Kokame K, Kato H, Miyata T. Identification of ERSE-II, a new cis-acting element responsible for the ATF6-dependent mammalian unfolded protein response[J]. J Biol Chem 2001;276(12):9199-205.
[136] Parker R, Phan T, Baumeister P, et al. Identification of TFII-I as the endoplasmic reticulum stress response element binding factor ERSF: its autoregulation by stress and interaction with ATF6[J]. Mol Cell Biol 2001;21 (9):3220-33.
[137] Ma Y, Hendershot LM. Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with othercellular stress pathways[J]. J Biol Chem 2004;279(14):13792-9.
[138] Zeng L, Lu M, Mori K, et al. ATF6 modulates SREBP2- mediated lipogenesis[J]. Embo J 2004;23(4):950-8.
[139] Glembotski CC. Endoplasmic reticulum stress in the heart[J]. Circ Res 2007;101(10):975-84.
[140] Yamamoto K, Yoshida H, Kokame K, et al. Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II[J]. J Biochem 2004;136(3):343-50.
[141] Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions[J]. J Clin Invest 2005;115(10):2656-64.
[142] Sundar Rajan S, Srinivasan V, Balasubramanyam M, et al. Endoplasmic reticulum (ER) stress & diabetes[J]. Indian J Med Res 2007;125(3):411-24.
[143] Cai L. Alcoholic cardiomyopathy: acetaldehyde, insulin insensitization and ER stress[J]. J Mol Cell Cardiol 2008;44(6):979-82.
[144] Hettiarachchi KD, Zimmet PZ, Myers MA. Dietary Toxins, Endoplasmic Reticulum (ER) Stress and Diabetes[J]. Curr Diabetes Rev 2008;4(2):146-56.
[145] Kaneto H, Matsuoka TA, Nakatani Y, et al. Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes[J]. J Mol Med 2005;83(6):429-39.
[146] Yoshida H. ER stress and diseases[J]. Febs J 2007;274(3):630-58.
[147] Li SY, Ren J. Cardiac overexpression of alcohol dehydrogenase exacerbates chronic ethanol ingestion-induced myocardial dysfunction and hypertrophy: role of insulin signaling and ER stress[J]. J Mol Cell Cardiol 2008;44(6):992-1001.
[148] Liu J, Mao W, Iwai C, et al. Adoptive passive transfer of rabbit beta1-adrenoceptor peptide immune cardiomyopathy into the Rag2-/- mouse: participation of the ER stress[J]. J Mol Cell Cardiol 2008;44(2):304-14.
[149] Mao W, Iwai C, Liu J, et al. Darbepoetin alfa exerts a cardioprotective effect in autoimmune cardiomyopathy via reduction of ER stress and activation of the PI3K/Akt andSTAT3 pathways[J]. J Mol Cell Cardiol 2008;45(2):250-60.
[150] Szegezdi E, Duffy A, O'Mahoney ME, et al. ER stress contributes to ischemia-induced cardiomyocyte apoptosis[J]. Biochem Biophys Res Commun 2006;349(4):1406-11.
[151] Bhimji S, Godin DV, McNeill JH. Myocardial ultrastructural changes in alloxan-induced diabetes in rabbits[J]. Acta Anat (Basel) 1986;125(3):195-200.
[152] Jackson CV, McGrath GM, Tahiliani AG, et al. A functional and ultrastructural analysis of experimental diabetic rat myocardium[J]. Manifestation of a cardiomyopathy. Diabetes 1985;34(9):876-83.
[153] Okada K, Minamino T, Tsukamoto Y, et al. Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis[J]. Circulation 2004;110(6):705-12
[154] Nakatani Y, Kaneto H, Kawamori D, et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes[J]. J Biol Chem 2005;280(1):847-51.
[155] Ma Y, Brewer JW, Diehl JA, et al. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response[J]. J Mol Biol 2002;318(5):1351-65.
[156] Wang XZ, Lawson B, Brewer JW, et al. Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153)[J]. Mol Cell Biol 1996;16(8):4273-80.
[157] Harding HP, Zhang Y, Zeng H, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress[J]. Mol Cell 2003;11(3):619-33.
[158] Pahl HL, Baeuerle PA. The ER-overload response: activation of NF-kappa B[J]. Trends Biochem Sci 1997;22(2):63-7.
[159] Hotamisligil GS. Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes[J]. Diabetes 2005;54Suppl 2:S73-8.
[160] Hetz C, Russelakis-Carneiro M, Maundrell K, et al. Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein[J]. Embo J 2003;22(20):5435-45.
[161] Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta[J]. Nature 2000;403(6765):98-103.
[162] Morishima N, Nakanishi K, Takenouchi H, et al. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12[J]. J Biol Chem 2002;277(37):34287-94.
[163] Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death[J]. Cell Death Differ 2006;13(3):363-73.
[164] Zhang K, Kaufman RJ. The unfolded protein response: a stress signaling pathway critical for health and disease[J]. Neurology 2006;66(2 Suppl 1):S102-9.
[165] Buytaert E, Callewaert G, Hendrickx N, et al. Role of endoplasmic reticulum depletion and multidomain proapoptotic BAX and BAK proteins in shaping cell death after hypericin-mediated photodynamic therapy[J]. Faseb J 2006;20(6):756-8.
[166] MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial[J]. Lancet 2002;360 (9326):23-33.
[167] Vega-Lopez S, Devaraj S, Jialal I. Oxidative stress and antioxidant supplementation in the management of diabetic cardiovascular disease[J]. J Investig Med 2004;52(1):24-32.
[168] Wiernsperger NF. Oxidative stress as a therapeutic target in diabetes: revisiting the controversy[J]. Diabetes Metab 2003;29(6):579-85.
[169] Cowell RM, Russell JW. Nitrosative injury and antioxidant therapy in the management of diabetic neuropathy[J]. J Investig Med 2004;52(1):33-44.
[170] Kang YJ. The antioxidant function of metallothionein in the heart[J]. Proc Soc ExpBiol Med 1999;222(3):263-73.
[171] Ceriello A. New insights on oxidative stress and diabetic complications may lead to a "causal" antioxidant therapy[J]. Diabetes Care 2003;26(5):1589-96.
[172] Cai L, Satoh M, Tohyama C, et al. Metallothionein in radiation exposure: its induction and protective role[J]. Toxicology 1999;132(2-3):85-98.
[173] Nath R, Kumar D, Li T, et al. Metallothioneins, oxidative stress and the cardiovascular system[J]. Toxicology 2000;155(1-3):17-26.
[174] Cai L, Cherian MG. Zinc-metallothionein protects from DNA damage induced by radiation better than glutathione and copper- or cadmium-metallothioneins[J]. Toxicol Lett 2003;136(3):193-8.
[175] Hamer DH. Metallothionein[J]. Annu Rev Biochem 1986;55:913-51.
[176] Vasak M. Advances in metallothionein structure and functions[J]. J Trace Elem Med Biol 2005;19(1):13-7.
[177] Rigby Duncan KE, Stillman MJ. Metal-dependent protein folding: metallation of metallothionein[J]. J Inorg Biochem 2006;100(12):2101-7.
[178] Marcellini M, Di Ciommo V, Callea F, et al. Treatment of Wilson's disease with zinc from the time of diagnosis in pediatric patients: a single-hospital, 10-year follow-up study[J]. J Lab Clin Med 2005;145(3):139-43.
[179] Hoogenraad TU. Paradigm shift in treatment of Wilson's disease: zinc therapy now treatment of choice[J]. Brain Dev 2006;28(3):141-6.
[180] Gonzalez BP, Nino Fong R, Gibson CJ, et al. Zinc supplementation decreases hepatic copper accumulation in LEC rat: a model of Wilson's disease[J]. Biol Trace Elem Res 2005;105(1-3):117-34.
[181] Krezel A, Maret W. Different redox states of metallothionein/thionein in biological tissue[J]. Biochem J 2007;402(3):551-8.
[182] Stitt MS, Wasserloos KJ, Tang X, et al. Nitric oxide-induced nuclear translocation of the metal responsive transcription factor, MTF-1 is mediated by zinc release frommetallothionein[J]. Vascul Pharmacol 2006;44(3):149-55.
[183] Casero E, Martin-Gago JA, Pariente F, et al Metal release in metallothioneins induced by nitric oxide: X-ray absorption spectroscopy study[J]. Eur Biophys J 2004;33(8):726-31.
[184] Quesada AR, Byrnes RW, Krezoski SO, et al. Direct reaction of H2O2 with sulfhydryl groups in HL-60 cells: zinc-metallothionein and other sites[J]. Arch Biochem Biophys 1996;334(2):241-50.
[185] Miura T, Muraoka S, Ogiso T. Antioxidant activity of metallothionein compared with reduced glutathione[J]. Life Sci 1997;60(21):PL 301-9.
[186] Cai L, Klein JB, Kang YJ. Metallothionein inhibits peroxynitrite-induced DNA and lipoprotein damage[J]. J Biol Chem 2000;275(50):38957-60.
[187] Thornalley PJ, Vasak M. Possible role for metallothionein in protection against radiation-induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals[J]. Biochim Biophys Acta 1985;827(1):36-44.
[188] Abel J, de Ruiter N. Inhibition of hydroxyl-radical-generated DNA degradation by metallothionein[J]. Toxicol Lett 1989;47(2):191-6.
[189] Sharma SK, Ebadi M. Metallothionein attenuates 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in dopaminergic neurons[J]. Antioxid Redox Signal 2003;5(3):251-64.
[190] Li X, Chen H, Epstein PN. Metallothionein protects islets from hypoxia and extends islet graft survival by scavenging most kinds of reactive oxygen species[J]. J Biol Chem 2004;279(1):765-71.
[191] Onosaka S, Cherian MG. The induced synthesis of metallothionein in various tissues of rat in response to metals. I. Effect of repeated injection of cadmium salts[J]. Toxicology 1981;22(2):91-101.
[192] Bauman JW, Liu J, Liu YP, et al. Increase in metallothionein produced by chemicals that induce oxidative stress[J]. Toxicol Appl Pharmacol 1991;110(2):347-54.
[193] Kang YJ, Chen Y, Yu A, et al. Overexpression of metallothionein in the heart of transgenic mice suppresses doxorubicin cardiotoxicity[J]. J Clin Invest 1997;100(6):1501-6.
[194] Zhou Z, Kang YJ. Immunocytochemical localization of metallothionein and its relation to doxorubicin toxicity in transgenic mouse heart[J]. Am J Pathol 2000;156(5):1653-62.
[195] Kang YJ, Zhou ZX, Wu H, et al. Metallothionein inhibits myocardial apoptosis in copper-deficient mice: role of atrial natriuretic peptide[J]. Lab Invest 2000;80(5):745-57.
[196] Kang YJ, Li Y, Sun X, et al. Antiapoptotic effect and inhibition of ischemia/reperfusion-induced myocardial injury in metallothionein-overexpressing transgenic mice[J]. Am J Pathol 2003;163(4):1579-86.
[197] Feng W, Benz FW, Cai J, et al. Metallothionein disulfides are present in metallothionein-overexpressing transgenic mouse heart and increase under conditions of oxidative stress[J]. J Biol Chem 2006;281(2):681-7.
[198] Cai L, Wang J, Li Y, et al. Inhibition of superoxide generation and associated nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy[J]. Diabetes 2005;54(6):1829-37.
[199] Cai L, Wang Y, Zhou G, et al. Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy[J]. J Am Coll Cardiol 2006;48(8):1688-97.
[200] Song Y, Wang J, Li Y, et al. Cardiac metallothionein synthesis in streptozotocin-induced diabetic mice, and its protection against diabetes-induced cardiac injury[J]. Am J Pathol 2005;167(1):17-26.
[201] Wang J, Song Y, Elsherif L, et al. Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation[J]. Circulation 2006;113(4):544-54.
[202] Feng W, Wang Y, Cai L, et al. Metallothionein rescues hypoxia-inducible factor-1 transcriptional activity in cardiomyocytes under diabetic conditions[J]. Biochem Biophys ResCommun 2007;360(1):286-9.
[203] Cai L. Suppression of nitrative damage by metallothionein in diabetic heart contributes to the prevention of cardiomyopathy[J]. Free Radic Biol Med 2006;41(6):851-61.
[204] Cai L. Diabetic cardiomyopathy and its prevention by metallothionein: experimental evidence, possible mechanisms and clinical implications[J]. Curr Med Chem 2007;14(20):2193-203.
[205] Szabo C, Mabley JG, Moeller SM, et al. Part I: pathogenetic role of peroxynitrite in the development of diabetes and diabetic vascular complications: studies with FP15, a novel potent peroxynitrite decomposition catalyst[J]. Mol Med 2002;8(10):571-80.
[206] Failla ML, Kiser RA. Altered tissue content and cytosol distribution of trace metals in experimental diabetes[J]. J Nutr 1981;111(11):1900-9.
[207] Failla ML, Kiser RA. Hepatic and renal metabolism of copper and zinc in the diabetic rat[J]. Am J Physiol 1983;244(2):E115-21.
[208] Chen ML, Failla ML. Metallothionein metabolism in the liver and kidney of the streptozotocin-diabetic rat[J]. Comp Biochem Physiol B 1988;90(2):439-45.
[209] Failla ML, Gardell CY. Influence of spontaneous diabetes on tissue status of zinc, copper, and manganese in the BB Wistar rat[J]. Proc Soc Exp Biol Med 1985;180(2):317-22.
[210] Kennedy ML, Failla ML. Zinc metabolism in genetically obese (ob/ob) mice[J]. J Nutr 1987;117(5):886-93.
[211] Apostolova MD, Chen S, Chakrabarti S, et al. High-glucose-induced metallothionein expression in endothelial cells: an endothelin-mediated mechanism[J]. Am J Physiol Cell Physiol 2001;281(3):C899-907.
[212] Meugnier E, Faraj M, Rome S, et al. Acute hyperglycemia induces a global downregulation of gene expression in adipose tissue and skeletal muscle of healthy subjects[J]. Diabetes 2007;56(4):992-9.
[213] Beltramini M, Zambenedetti P, Raso M, et al. The effect of Zn(II) and streptozotocin administration in the mouse brain[J]. Brain Res 2006;1109(1):207-18.
[214] Lecker SH, Jagoe RT, Gilbert A, et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression[J]. Faseb J 2004;18(1):39-51.
[215] Gerhardinger C, Costa MB, Coulombe MC, et al. Expression of acute-phase response proteins in retinal Muller cells in diabetes[J]. Invest Ophthalmol Vis Sci 2005;46(1):349-57.
[216] Puskas LG, Nagy ZB, Giricz Z, et al. Cholesterol diet-induced hyperlipidemia influences gene expression pattern of rat hearts: a DNA microarray study[J]. FEBS Lett 2004;562(1-3):99-104.
[217] Uriu-Adams JY, Rucker RB, Commisso JF, et al. Diabetes and dietary copper alter 67Cu metabolism and oxidant defense in the rat[J]. J Nutr Biochem 2005;16(5):312-20.
[218] Liang Q, Carlson EC, Donthi RV, et al. Overexpression of metallothionein reduces diabetic cardiomyopathy[J]. Diabetes 2002;51 (1):174-81.
[219] Ceylan-Isik AF, LaCour KH, Ren J. Sex difference in cardiomyocyte function in normal and metallothionein transgenic mice: the effect of diabetes mellitus[J]. J Appl Physiol 2006;100(5):1638-46.
[220] Fang CX, Dong F, Ren BH, et al. Metallothionein alleviates cardiac contractile dysfunction induced by insulin resistance: role of Akt phosphorylation, PTB1B, PPARgamma and c-Jun[J]. Diabetologia 2005;48(11):2412-21.
[221] Ye G, Metreveli NS, Donthi RV, et al. Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes[J]. Diabetes 2004;53(5):1336-43.
[222] Shen X, Zheng S, Metreveli NS, et al. Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy[J]. Diabetes 2006;55(3):798- 805.
[223] Privratsky JR, Wold LE, Sowers JR, et al. AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase[J]. Hypertension 2003;42(2):206-12.
[224] Ye G, Metreveli NS, Ren J, et al. Metallothionein prevents diabetes- induceddeficits in cardiomyocytes by inhibiting reactive oxygen species production[J]. Diabetes 2003;52(3):777-83.
[225] Wold LE, Ceylan-Isik AF, Fang CX, et al. Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme[J]. Free Radic Biol Med 2006;40(8):1419-29.
[226] Trost SU, Belke DD, Bluhm WF, et al. Overexpression of the sarcoplasmic reticulum Ca(2+)-ATPase improves myocardial contractility in diabetic cardiomyopathy[J]. Diabetes 2002;51(4):1166-71.
[227] Maier LS, Wahl-Schott C, Horn W, et al. Increased SR Ca2+ cycling contributes to improved contractile performance in SERCA2a-overexpressing transgenic rats[J]. Cardiovasc Res 2005;67(4):636-46.
[228] Kralik PM, Ye G, Metreveli NS, et al. Cardiomyocyte dysfunction in models of type 1 and type 2 diabetes[J]. Cardiovasc Toxicol 2005;5(3):285-92.
[229] Ayaz M, Turan B. Selenium prevents diabetes-induced alterations in [Zn2+]i and metallothionein level of rat heart via restoration of cell redox cycle[J]. Am J Physiol Heart Circ Physiol 2006;290(3):H1071-80.
[230] Korichneva I. Zinc dynamics in the myocardial redox signaling network[J]. Antioxid Redox Signal 2006;8(9-10):1707-21.
[231] Feng W, Cai J, Pierce WM, et al. Metallothionein transfers zinc to mitochondrial aconitase through a direct interaction in mouse hearts[J]. Biochem Biophys Res Commun 2005;332(3):853-8.
[232] Song Y, Wang J, Li XK, et al. Zinc and the diabetic heart[J]. Biometals 2005;18(4):325-32.
[233] Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of the heart in diabetes: Part I: general concepts[J]. Circulation 2002;105(14):1727-33.
[234] DeBosch B, Sambandam N, Weinheimer C, et al. Akt2 regulates cardiacmetabolism and cardiomyocyte survival[J]. J Biol Chem 2006;281 (43):32841-51.
[235] Muslin AJ, DeBosch B. Role of Akt in cardiac growth and metabolism[J]. Novartis Found Symp 2006;274:118-26; discussion 26-31,52-5,272-6.
[236] Miranda ER, Dey CS. Effect of chromium and zinc on insulin signaling in skeletal muscle cells[J]. Biol Trace Elem Res 2004;101(1):19-36.
[237] Simon SF, Taylor CG. Dietary zinc supplementation attenuates hyperglycemia in db/db mice[J]. Exp Biol Med (Maywood) 2001;226(1):43-51.
[238] Canatan H, Bakan I, Akbulut M, et al. Relationship among levels of leptin and zinc, copper, and zinc/copper ratio in plasma of patients with essential hypertension and healthy normotensive subjects[J]. Biol Trace Elem Res 2004;100(2):117-23.
[239] Anetor JI, Senjobi A, Ajose OA, et al. Decreased serum magnesium and zinc levels: atherogenic implications in type-2 diabetes mellitus in Nigerians[J]. Nutr Health 2002;16(4):291-300.
[240] Roussel AM, Kerkeni A, Zouari N, et al. Antioxidant effects of zinc supplementation in Tunisians with type 2 diabetes mellitus[J]. J Am Coll Nutr 2003;22(4):316-21.
[241] Kajanachumpol S, Srisurapanon S, Supanit I, et al. Effect of zinc supplementation on zinc status, copper status and cellular immunity in elderly patients with diabetes mellitus[J]. J Med Assoc Thai 1995;78(7):344-9.
[242] Al-Maroof RA, Al-Sharbatti SS. Serum zinc levels in diabetic patients and effect of zinc supplementation on glycemic control of type 2 diabetics[J]. Saudi Med J 2006;27(3):344-50.
[243] Kadhim HM, Ismail SH, Hussein KI, et al. Effects of melatonin and zinc on lipid profile and renal function in type 2 diabetic patients poorly controlled with metformin[J]. J Pineal Res 2006;41(2):189-93.
[244] Farvid MS, Jalali M, Siassi F, et al. Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes[J]. Diabetes Care 2005;28(10):2458-64.
[245] Faure P, Benhamou PY, Perard A, et al. Lipid peroxidation in insulin-dependent diabetic patients with early retina degenerative lesions: effects of an oral zinc supplementation[J]. Eur J Clin Nutr 1995;49(4):282-8.
[246] Gupta R, Garg VK, Mathur DK, et al. Oral zinc therapy in diabetic neuropathy[J]. J Assoc Physicians India 1998;46(11):939-42.
[247] Hayee MA, Mohammad QD, Haque A. Diabetic neuropathy and zinc therapy[J]. Bangladesh Med Res Counc Bull 2005;31(2):62-7.
[248] Kosar F, Sahin I, Taskapan C, et al. Trace element status (Se, Zn, Cu) in heart failure[J]. Anadolu Kardiyol Derg 2006;6(3):216-20.
[249] Giacconi R, Cipriano C, Muti E, et al. Novel -209A/G MT2A polymorphism in old patients with type 2 diabetes and atherosclerosis: relationship with inflammation (IL-6) and zinc[J]. Biogerontology 2005;6(6):407-13.
[250] Soinio M, Marniemi J, Laakso M, et al. Serum zinc level and coronary heart disease events in patients with type 2 diabetes[J]. Diabetes Care 2007;30(3):523-8.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |