PARP抑制剂延缓高同型半胱氨酸血症诱导ApoE-/-小鼠动脉粥样硬化斑块进展
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摘要
第一部分PARP抑制剂降低高同型半胱氨酸血症诱导ApoE-／-小鼠动脉粥样硬化斑块面积
目的高同型半胱氨酸血症(hyperhomocysteinemia，Hhcy)是动脉粥样硬化的一个重要而独立的危险因子。最近的研究表明多聚ADP核糖合成酶[Poly(ADP-ribose)polymerase，PARP]的活化与Hhcy诱导的内皮功能障碍有关，而后者是Hhcy影响动脉粥样硬化进程的重要机制之一。因此，我们检测PARP抑制剂是否能够降低Hhcy诱导的动脉粥样硬化实验动物模型粥样斑块的面积。
方法健康雄性6周龄纯合子ApoE基因缺陷小鼠(ApoE-／-)随机分为普通饮食组或高甲硫氨酸饮食组，每组再分别给予隔天腹腔注射PBS溶解的10mg／kg PARP抑制剂3-aminobenzamide(3-AB)或生理盐水，持续12周。检测血脂及血浆同型半胱氨酸(homocysteine，Hcy)含量，分离心脏及主动脉，测量主动脉窦斑块面积，通过实时定量PCR及Western Blot等方法检测主动脉斑块局部氧化应激相关NADPH氧化酶亚单位p47~(phox)含量、PARP活性及表达。
结果高甲硫氨酸饮食诱导ApoE-／-小鼠产生Hhcy，促进氧化应激相关DNA损伤及PARP活化，显著增加粥样斑块面积。喂以普通饮食的ApoE-／-小鼠能够自发产生高脂血症，PARP抑制剂3-AB虽然对其抑制效果不明显，却能在不影响血浆同型半胱氨酸水平和脂质含量的情况下，有效抑制Hhcy诱导的PARP活化，显著降低ApoE-／-小鼠粥样斑块面积达40％。
结论PARP抑制剂3-AB显著降低Hhcy诱导的ApoE-／-小鼠动脉粥样硬化斑块面积，可作为有效抑制粥样斑块进程的治疗方法之一。
第二部分PARP抑制剂抑制动脉粥样硬化斑块内NF-κB活化及后续炎症因子表达
目的检测多聚ADP核糖合成酶[Poly(ADP-ribose)polymerase，PARP]抑制剂3-aminobenzamide(3-AB)是否能够抑制高同型半胱氨酸血症(hyperhomocysteinemia，Hhcy)诱导的ApoE基因缺陷小鼠(ApoE-／-)动脉粥样硬化斑块内核因子-κB(nuclearfactor-κB，NF-κB)核转移及后续炎症因子的表达。
方法健康雄性6周龄纯合子ApoE基因缺陷小鼠(ApoE-／-)随机分为普通饮食组或高甲硫氨酸饮食组，每组再分别给予隔天腹腔注射PBS溶解的10mg／kg PARP抑制剂3-aminobenzamide(3-AB)或生理盐水，持续12周。检测血脂及血浆同型半胱氨酸(homocysteine，Hcy)含量，分离心脏及主动脉，通过Western Blot，免疫组化及实时定量PCR等方法检测主动脉斑块局部胞浆、胞核内及总蛋白中的NF-κB p65、κB抑制蛋白(IκB)及磷酸化IκB(p-IκB)的表达，检测斑块局部炎症因子VCAM-1和MCP-1的表达。
结果高甲硫氨酸饮食喂养的ApoE-／-小鼠产生Hhcy，促进主动脉斑块细胞胞核内NF-κB p65及总蛋白中p-IκB的表达增高，即促进NF-κB的核转移，继而提高斑块局部VCAM-1和MCP-1的表达；喂以普通饮食的ApoE-／-小鼠能够自发产生高脂血症，PARP抑制剂3-AB虽然对其抑制效果不明显，却能在不影响血浆同型半胱氨酸水平和脂质含量的情况下，有效抑制伴有Hhcy小鼠NF-κB核内表达及p-IκB的含量，增加胞浆内NF-κB的表达，从而显著降低粥样斑块内炎症因子的表达。
结论PARP抑制剂3-AB显著抑制Hhcy诱导的ApoE-／-小鼠动脉粥样硬化斑块内NF-κB核转移及后续炎症因子的表达。
第三部分PARP抑制剂促进动脉粥样硬化斑块内细胞凋亡
目的检测多聚ADP核糖合成酶[Poly(ADP-ribose)polymerase，PARP]抑制剂3-aminobenzamide(3-AB)对高同型半胱氨酸血症(hyperhomocysteinemia，Hhcy)诱导的ApoE基因缺陷小鼠(ApoE-／-)动脉粥样硬化斑块内细胞凋亡的影响。
方法健康雄性6周龄纯合子ApoE基因缺陷小鼠(ApoE-／-)随机分为普通饮食组或高甲硫氨酸饮食组，每组再分别给予隔天腹腔注射PBS溶解的10mg／kg PARP抑制剂3-aminobenzamide(3-AB)或生理盐水，持续12周。检测血脂及血浆同型半胱氨酸(homocysteine，Hcy)含量，分离心脏及主动脉，检测粥样硬化斑块内细胞凋亡情况及相关caspase-3酶蛋白表达情况。
结果高甲硫氨酸饮食喂养的ApoE-／-小鼠产生Hhcy，促进主动脉斑块内caspase-3的活化及细胞凋亡；PARP抑制剂3-AB虽然对普通饮食小鼠影响效果不明显，却能在不影响血浆同型半胱氨酸水平和脂质含量的情况下，明显促进Hhcy诱导小鼠斑块内35-KD caspase-3原始蛋白的消耗，即促进caspase-3的活化，进而促进斑块内细胞死亡模式更加倾向于凋亡。
结论PARP抑制剂3-AB能够促进Hhcy诱导的ApoE-／-小鼠动脉粥样硬化斑块内细胞凋亡。
PartⅠPARP Inhibition Decreases Atherosclerotic Lesion size inApoE-/- Mice with Hyperhomocysteinemia
Objective Hyperhomocysteinemia (Hhcy) is an important and independent risk factor foratherosclerosis.Recent studies have shown that Poly (ADP-ribose) polymerase (PARP)activation may be associated with Hhcy-induced endothelial dysfunction,which is animportant mechanism for Hhcy to affect atherosclerotic progress.Thus we investigatedwhether PARP inhibitors may decrease the atherosclerotic plaque size in anHhcy-induced experimental animal model with atherosclerosis.
Methods Six-week-old homozygous apolipoprotein E-deficient (ApoE-/-) male mice fedwith a normal diet or high methionine-diet were randomly received intraperitonealinjections of 10mg/kg 3-aminobenzamide (3-AB,a kind of PARP inhibitor) dissolvedin PBS,or physiological saline every other day for 12 weeks.Plasma homocysteine(Hcy) levels and lipids contents were measured.Atherosclerotic lesion sizes,thephosphorylation of p47~(phox) subunit of NADPH oxidase and the expression of PARPprotein and PARP activity were detected.
Results Our data demonstrated that the ApoE-/- mice fed with high methionine-dietgenerated Hhcy,which subsequently promoted the oxidative stress-associated DNAdamage and PARP activation,increased atherosclerotic lesion size significantly.Although PARP inhibition by 3-AB did not markedly inhibit the plaque developmentin ApoE-/- mice with spontaneous hyperlipidemia by feeding with a normal diet,itsignificantly reduced atherosclerotic lesion size by 40% in Hhcy-inducedatherosclerosis without affecting plasma homocysteine levels and lipid contents,effectively suppressed PARP activation.
Conclusions Our results suggest that PARP inhibition attenuates the atherosclerotic plaquesize in the hyperhomocysteinemic conditions,indicates 3-AB may prove beneficial forthe treatment of atherosclerosis.
PartⅡPARP Inhibition Suppress Nuclear Translocation of
NF-κB and Subsequent Production of Inflammatory Factors withinAtherosclerotic Plaques
Objective To investigate whether PARP [Poly (ADP-ribose) polymerase] inhibitor3-aminobenzamide (3-AB) may suppress the nuclear translocation of nuclear factor(NF)-κB and subsequent production of inflammatory factors in the plaque lesions in anHhcy (hyperhomocysteinemia)-induced experimental animal model withatherosclerosis.
Methods Six-week-old homozygous apolipoprotein E-deficient (ApoE-/-) male mice fedwith a normal diet or high methionine-diet were randomly received intraperitonealinjections of 10mg/kg 3-aminobenzamide (3-AB,a kind of PARP inhibitor) dissolvedin PBS,or physiological saline every other day for 12 weeks.Plasma homocysteine(Hcy) levels and lipids contents were measured.Then hearts and aortas were removedrapidly.The thoracic and abdominal aorta was quick-frozen in nitrogen for laterextraction of protein and RNA.The expression of NF-κB p65、inhibitors ofκB (IκB),and phospho-inhibitors ofκB (p-IκB) in total proteins,cytoplasmic extracts andnuclear extracts was measured.The expression of VCAM-1 and MCP-1 withinplaques was also detected by Immunohistochemistry analysis,Westem Blot analysisand real-time reverse-transcription PCR.
Results Our data demonstrated that the ApoE-/- mice fed with high methionine-dietgenerated Hhcy,which significantly increased the expression of NF-κB p65 in nuclearextracts and p-IκB in total proteins,promoted the nuclear translocation of NF-κB,thereby increased the subsequent production of inflammatory factors within plaquessuch as VCAM-1 and MCP-1.Although PARP inhibition by 3-AB did not markedlyinhibit the nuclear translocation of NF-κB in ApoE-/- mice with spontaneous hyperlipidemia by feeding with a normal diet,it significantly reduced the activity ofNF-κB in Hhcy-induced atherosclerosis without affecting plasma homocysteine levelsand lipid contents,effectively suppressed subsequent production of VCAM-1 andMCP-1.
Conclusions Our results suggest that PARP inhibition suppress the nuclear translocation ofNF-κB and subsequent production of inflammatory factors in the atheroscleroticplaques in the hyperhomocysteinemic conditions.
PartⅢPARP Inhibition Promotes Apoptosis withinAtherosclerotic Plaques
Objective To investigate whether PARP [Poly (ADP-ribose) polymerase] inhibitor3-aminobenzamide (3-AB) effects on the apoptosis within the atherosclerotic plaquesin an Hhcy (hyperhomocysteinemia)-induced experimental animal model withatherosclerosis.
Methods Six-week-old homozygous apolipoprotein E-deficient (ApoE-/-) male mice fedwith a normal diet or high methionine-diet were randomly received intraperitonealinjections of 10mg/kg 3-aminobenzamide (3-AB,a kind of PARP inhibitor) dissolvedin PBS,or physiological saline every other day for 12 weeks.Plasma homocysteine(Hcy) levels and lipids contents were measured.Then hearts and aortas were removedrapidly.The thoracic and abdominal aorta was quick-frozen in nitrogen for laterextraction of protein and RNA.Apoptotic cells were detected by Apoptosis DetectionKit;the expression of caspase-3 within plaques was measured by Western Blotanalysis.
Results Our data demonstrated that the ApoE-/- mice fed with high methionine-dietgenerated Hhcy.The apoptotic cells were highly increased in Hhcy condition whichwas detected by Apoptosis Detection Kit.Although PARP inhibition by 3-AB did notmarkedly have effect on apoptosis in ApoE-/- mice with spontaneous hyperlipidemiaby feeding with a normal diet,it significantly incrased the depletion of na(?)ve caspase-3, aggravated the caspase-3 activation,made the mode of cell death be prone to apoptosisin Hhcy-induced atherosclerosis without affecting plasma homocysteine levels andlipid contents.
Conclusions Our results suggest that PARP inhibition aggravated the caspase-3 activation,promoted the apoptosis in the atherosclerotic plaques in the hyperhomocysteinemicconditions.
目的高同型半胱氨酸血症(hyperhomocysteinemia，Hhcy)是动脉粥样硬化的一个重要而独立的危险因子。最近的研究表明多聚ADP核糖合成酶[Poly(ADP-ribose)polymerase，PARP]的活化与Hhcy诱导的内皮功能障碍有关，而后者是Hhcy影响动脉粥样硬化进程的重要机制之一。因此，我们检测PARP抑制剂是否能够降低Hhcy诱导的动脉粥样硬化实验动物模型粥样斑块的面积。
方法健康雄性6周龄纯合子ApoE基因缺陷小鼠(ApoE-／-)随机分为普通饮食组或高甲硫氨酸饮食组，每组再分别给予隔天腹腔注射PBS溶解的10mg／kg PARP抑制剂3-aminobenzamide(3-AB)或生理盐水，持续12周。检测血脂及血浆同型半胱氨酸(homocysteine，Hcy)含量，分离心脏及主动脉，测量主动脉窦斑块面积，通过实时定量PCR及Western Blot等方法检测主动脉斑块局部氧化应激相关NADPH氧化酶亚单位p47~(phox)含量、PARP活性及表达。
结果高甲硫氨酸饮食诱导ApoE-／-小鼠产生Hhcy，促进氧化应激相关DNA损伤及PARP活化，显著增加粥样斑块面积。喂以普通饮食的ApoE-／-小鼠能够自发产生高脂血症，PARP抑制剂3-AB虽然对其抑制效果不明显，却能在不影响血浆同型半胱氨酸水平和脂质含量的情况下，有效抑制Hhcy诱导的PARP活化，显著降低ApoE-／-小鼠粥样斑块面积达40％。
结论PARP抑制剂3-AB显著降低Hhcy诱导的ApoE-／-小鼠动脉粥样硬化斑块面积，可作为有效抑制粥样斑块进程的治疗方法之一。
第二部分PARP抑制剂抑制动脉粥样硬化斑块内NF-κB活化及后续炎症因子表达
目的检测多聚ADP核糖合成酶[Poly(ADP-ribose)polymerase，PARP]抑制剂3-aminobenzamide(3-AB)是否能够抑制高同型半胱氨酸血症(hyperhomocysteinemia，Hhcy)诱导的ApoE基因缺陷小鼠(ApoE-／-)动脉粥样硬化斑块内核因子-κB(nuclearfactor-κB，NF-κB)核转移及后续炎症因子的表达。
方法健康雄性6周龄纯合子ApoE基因缺陷小鼠(ApoE-／-)随机分为普通饮食组或高甲硫氨酸饮食组，每组再分别给予隔天腹腔注射PBS溶解的10mg／kg PARP抑制剂3-aminobenzamide(3-AB)或生理盐水，持续12周。检测血脂及血浆同型半胱氨酸(homocysteine，Hcy)含量，分离心脏及主动脉，通过Western Blot，免疫组化及实时定量PCR等方法检测主动脉斑块局部胞浆、胞核内及总蛋白中的NF-κB p65、κB抑制蛋白(IκB)及磷酸化IκB(p-IκB)的表达，检测斑块局部炎症因子VCAM-1和MCP-1的表达。
结果高甲硫氨酸饮食喂养的ApoE-／-小鼠产生Hhcy，促进主动脉斑块细胞胞核内NF-κB p65及总蛋白中p-IκB的表达增高，即促进NF-κB的核转移，继而提高斑块局部VCAM-1和MCP-1的表达；喂以普通饮食的ApoE-／-小鼠能够自发产生高脂血症，PARP抑制剂3-AB虽然对其抑制效果不明显，却能在不影响血浆同型半胱氨酸水平和脂质含量的情况下，有效抑制伴有Hhcy小鼠NF-κB核内表达及p-IκB的含量，增加胞浆内NF-κB的表达，从而显著降低粥样斑块内炎症因子的表达。
结论PARP抑制剂3-AB显著抑制Hhcy诱导的ApoE-／-小鼠动脉粥样硬化斑块内NF-κB核转移及后续炎症因子的表达。
第三部分PARP抑制剂促进动脉粥样硬化斑块内细胞凋亡
目的检测多聚ADP核糖合成酶[Poly(ADP-ribose)polymerase，PARP]抑制剂3-aminobenzamide(3-AB)对高同型半胱氨酸血症(hyperhomocysteinemia，Hhcy)诱导的ApoE基因缺陷小鼠(ApoE-／-)动脉粥样硬化斑块内细胞凋亡的影响。
方法健康雄性6周龄纯合子ApoE基因缺陷小鼠(ApoE-／-)随机分为普通饮食组或高甲硫氨酸饮食组，每组再分别给予隔天腹腔注射PBS溶解的10mg／kg PARP抑制剂3-aminobenzamide(3-AB)或生理盐水，持续12周。检测血脂及血浆同型半胱氨酸(homocysteine，Hcy)含量，分离心脏及主动脉，检测粥样硬化斑块内细胞凋亡情况及相关caspase-3酶蛋白表达情况。
结果高甲硫氨酸饮食喂养的ApoE-／-小鼠产生Hhcy，促进主动脉斑块内caspase-3的活化及细胞凋亡；PARP抑制剂3-AB虽然对普通饮食小鼠影响效果不明显，却能在不影响血浆同型半胱氨酸水平和脂质含量的情况下，明显促进Hhcy诱导小鼠斑块内35-KD caspase-3原始蛋白的消耗，即促进caspase-3的活化，进而促进斑块内细胞死亡模式更加倾向于凋亡。
结论PARP抑制剂3-AB能够促进Hhcy诱导的ApoE-／-小鼠动脉粥样硬化斑块内细胞凋亡。
PartⅠPARP Inhibition Decreases Atherosclerotic Lesion size inApoE-/- Mice with Hyperhomocysteinemia
Objective Hyperhomocysteinemia (Hhcy) is an important and independent risk factor foratherosclerosis.Recent studies have shown that Poly (ADP-ribose) polymerase (PARP)activation may be associated with Hhcy-induced endothelial dysfunction,which is animportant mechanism for Hhcy to affect atherosclerotic progress.Thus we investigatedwhether PARP inhibitors may decrease the atherosclerotic plaque size in anHhcy-induced experimental animal model with atherosclerosis.
Methods Six-week-old homozygous apolipoprotein E-deficient (ApoE-/-) male mice fedwith a normal diet or high methionine-diet were randomly received intraperitonealinjections of 10mg/kg 3-aminobenzamide (3-AB,a kind of PARP inhibitor) dissolvedin PBS,or physiological saline every other day for 12 weeks.Plasma homocysteine(Hcy) levels and lipids contents were measured.Atherosclerotic lesion sizes,thephosphorylation of p47~(phox) subunit of NADPH oxidase and the expression of PARPprotein and PARP activity were detected.
Results Our data demonstrated that the ApoE-/- mice fed with high methionine-dietgenerated Hhcy,which subsequently promoted the oxidative stress-associated DNAdamage and PARP activation,increased atherosclerotic lesion size significantly.Although PARP inhibition by 3-AB did not markedly inhibit the plaque developmentin ApoE-/- mice with spontaneous hyperlipidemia by feeding with a normal diet,itsignificantly reduced atherosclerotic lesion size by 40% in Hhcy-inducedatherosclerosis without affecting plasma homocysteine levels and lipid contents,effectively suppressed PARP activation.
Conclusions Our results suggest that PARP inhibition attenuates the atherosclerotic plaquesize in the hyperhomocysteinemic conditions,indicates 3-AB may prove beneficial forthe treatment of atherosclerosis.
PartⅡPARP Inhibition Suppress Nuclear Translocation of
NF-κB and Subsequent Production of Inflammatory Factors withinAtherosclerotic Plaques
Objective To investigate whether PARP [Poly (ADP-ribose) polymerase] inhibitor3-aminobenzamide (3-AB) may suppress the nuclear translocation of nuclear factor(NF)-κB and subsequent production of inflammatory factors in the plaque lesions in anHhcy (hyperhomocysteinemia)-induced experimental animal model withatherosclerosis.
Methods Six-week-old homozygous apolipoprotein E-deficient (ApoE-/-) male mice fedwith a normal diet or high methionine-diet were randomly received intraperitonealinjections of 10mg/kg 3-aminobenzamide (3-AB,a kind of PARP inhibitor) dissolvedin PBS,or physiological saline every other day for 12 weeks.Plasma homocysteine(Hcy) levels and lipids contents were measured.Then hearts and aortas were removedrapidly.The thoracic and abdominal aorta was quick-frozen in nitrogen for laterextraction of protein and RNA.The expression of NF-κB p65、inhibitors ofκB (IκB),and phospho-inhibitors ofκB (p-IκB) in total proteins,cytoplasmic extracts andnuclear extracts was measured.The expression of VCAM-1 and MCP-1 withinplaques was also detected by Immunohistochemistry analysis,Westem Blot analysisand real-time reverse-transcription PCR.
Results Our data demonstrated that the ApoE-/- mice fed with high methionine-dietgenerated Hhcy,which significantly increased the expression of NF-κB p65 in nuclearextracts and p-IκB in total proteins,promoted the nuclear translocation of NF-κB,thereby increased the subsequent production of inflammatory factors within plaquessuch as VCAM-1 and MCP-1.Although PARP inhibition by 3-AB did not markedlyinhibit the nuclear translocation of NF-κB in ApoE-/- mice with spontaneous hyperlipidemia by feeding with a normal diet,it significantly reduced the activity ofNF-κB in Hhcy-induced atherosclerosis without affecting plasma homocysteine levelsand lipid contents,effectively suppressed subsequent production of VCAM-1 andMCP-1.
Conclusions Our results suggest that PARP inhibition suppress the nuclear translocation ofNF-κB and subsequent production of inflammatory factors in the atheroscleroticplaques in the hyperhomocysteinemic conditions.
PartⅢPARP Inhibition Promotes Apoptosis withinAtherosclerotic Plaques
Objective To investigate whether PARP [Poly (ADP-ribose) polymerase] inhibitor3-aminobenzamide (3-AB) effects on the apoptosis within the atherosclerotic plaquesin an Hhcy (hyperhomocysteinemia)-induced experimental animal model withatherosclerosis.
Methods Six-week-old homozygous apolipoprotein E-deficient (ApoE-/-) male mice fedwith a normal diet or high methionine-diet were randomly received intraperitonealinjections of 10mg/kg 3-aminobenzamide (3-AB,a kind of PARP inhibitor) dissolvedin PBS,or physiological saline every other day for 12 weeks.Plasma homocysteine(Hcy) levels and lipids contents were measured.Then hearts and aortas were removedrapidly.The thoracic and abdominal aorta was quick-frozen in nitrogen for laterextraction of protein and RNA.Apoptotic cells were detected by Apoptosis DetectionKit;the expression of caspase-3 within plaques was measured by Western Blotanalysis.
Results Our data demonstrated that the ApoE-/- mice fed with high methionine-dietgenerated Hhcy.The apoptotic cells were highly increased in Hhcy condition whichwas detected by Apoptosis Detection Kit.Although PARP inhibition by 3-AB did notmarkedly have effect on apoptosis in ApoE-/- mice with spontaneous hyperlipidemiaby feeding with a normal diet,it significantly incrased the depletion of na(?)ve caspase-3, aggravated the caspase-3 activation,made the mode of cell death be prone to apoptosisin Hhcy-induced atherosclerosis without affecting plasma homocysteine levels andlipid contents.
Conclusions Our results suggest that PARP inhibition aggravated the caspase-3 activation,promoted the apoptosis in the atherosclerotic plaques in the hyperhomocysteinemicconditions.
引文
1. Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049-1057.
2. Tawakol A, Omland T, Gerhard M, et al. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation.1997;95:1119-1121.
3. Lang D, Kredan MB, Moat SJ, et al. Homocysteine-induced inhibition of endothelium-dependent relaxation in rabbit aorta: Role for superoxide anions.Arterioscler Thromb Vasc Biol. 2000;20:422-427.
4. McDowell IF, Lang D. Homocysteine and endothelial dysfunction: A link with cardiovascular disease. J Nutr. 2000;130(2S suppl):369S-372S.
5. Harrison DG, Cai H, Landmesser U, et al. Interactions of angiotensin Ⅱ with NAD(P)H oxidase, oxidant stress and cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2003;4:51-61.
6. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315-424.
7. Rubbo H, O'Donnell V. Nitric oxide, peroxynitrite and lipoxygenase in atherogenesis: Mechanistic insights. Toxicology. 2005;208:305-317.
8. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: The role of poly (ADP -ribose) polymerase activation. Nat Med. 2001;7:108-113.
9. Pieper AA, Walles T, Wei G, et al. Myocardial postischemic injury is reduced by poly (ADP -ribose) polymerase-1 gene disruption. Mol Med. 2006;6:271-281.
10. Sharp C, Warren A, Oshima T, et al. Poly ADP -ribose polymerase inhibitors prevent the upregulation of ICAM-1 and E-selectin in response to Th1 cytokine stimulation. Inflammation. 2001;25:157-163.
11. Hassa PO, Hottiger MO. The functional role of poly (ADP -ribose) polymerase 1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell Mol Life Sci. 2002;59:1534-1553.
12. Carrillo A, Monreal Y, Ramirez P, et al. Transcription regulation of TNF-alpha-early response genes by poly (ADP -ribose) polymerase-1 in murine heart endothelial cells. Nucleic Acids Res. 2004;32:757-766.
13. Chiarugi A, Moskowitz MA. Poly (ADP -ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J Neurochem. 2003;85:306-317.
14. Le Page C, Sanceau J, Drapier JC, et al. Inhibition of ADP -ribosylation impair inducible nitric oxide synthase gene transcription through inhibition of NF kappa B activation. Biochem Biophys Res Commum. 1998;243:451-457.
15. Oliver FJ, Menissier-de Murcia J, Nacci C, et al. Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP -ribose) polymerase-1deficent mice. EMBO J. 1999;18:4446-4454.
16. Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation. 2002;106:927-932.
17. Oumouna-Benachour K, Hans CP, Suzuki Y, et al. Poly(ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death. Circulation. 2007;115(8):2442-50.
18. Zingarellli B, Hake PW, O'Connor M, et al. Absence of Poly(ADP-ribose) polymerase-1 alters nuclear factor-kappa B activation and gene expression of apoptosis regulators after reperfusion injury. Mol Med. 2003;9:143-153.
1. Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995; 274:1049-1057.
2. Harrison DG, Cai H, Landmesser U, et al. Interactions of angiotensin Ⅱ with NAD(P)H oxidase, oxidant stress and cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2003; 4:51-61.
3. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: The role of poly (ADP -ribose) polymerase activation. Nat Med. 2001; 7:108-113.
4. Pieper AA, Walles T, Wei G, et al. Myocardial postischemic injury is reduced by poly (ADP -ribose) polymerase-1 gene disruption. Mol Med. 2006; 6:271-281.
5. Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation. 2002;106:927-932.
6. Inoue S, Egashira K, Ni W, et al. Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein E-knockout mice. Circulation. 2002; 106:2700-2706.
7. Paigen B, Morrow A, Holmes PA, et al. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis. 1987;68:231-240.
8. Cheng X, Chen Y, Xie JJ, et al. Suppressive oligodeoxynucleotides inhibit atherosclerosis in ApoE (-/-) mice through modulation of Th1/Th2 balance. J Mol Cell Cardiol. 2008;45(2): 168-75.
9. Ni W, Egashira K, Kitamoto S, et al. New Anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice. Circulation.2001; 103:2096-2101.
10. Siow YL, Au-Yeung KK, Woo CW, et al. Homocysteine stimulates phosphorylation of NAPDH oxidase p47phox and p67phox subunits in monocytes via protein kinase Cbeta activation. Biochem J. 2006;398(1):73-82.
11. Tasatargil A, Dalaklioglu S, Sadan G. Poly (ADP-ribose) polymerase inhibition prevents homocysteine-induced endothelial dysfunction in the isolated rat aorta. Pharmacology. 2004;72(2):99-105.
12. Zhou J, Mφller J, Danielsen CC, et al. Dietary supplementation with menthionine and homocysteine promotes early athrosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2001 ;21:1470-1476.
13. Zhou J, Mφller J, Ritskes-Hoitinga M, et al. Effect of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice. Atheroscletosis. 2003;168:255-262.
14. Wang H, Jiang X, Yang F, et al. Hyperhomocysteinemia accelerates atherosclerosis in cystathiorine betasynthase and apolipoprotein E double knock-out mice with and without dietary pertyrbation. Blood. 2003;101:3901-3907.
15. Hofmann MA, Lalla E, Lu Y, et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001;107:675-683.
16. Oumouna-Benachour K, Hans CP, Suzuki Y, et al. Poly (ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death. Circulation. 2007; 115(8):2442-50.
17. Werns SW, Walton JA, Hsia HH, et al. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation. 1989;79:287-291.
18. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Chin Invest. 1986;77:1370-1376.
19. Szabo C, Dawson VL. Role of poly (ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci. 1998;19:287-298.
20. Pieper AA, Brat DJ, Krug DK, et al. Poly (ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. Proc Natl Acad Sci USA. 1999;96:3059-3064.
21. Pacher P, Mabley JG, Soriano FG, et al. Endothelial dysfunction in aging animals: The role of Poly(ADP-ribose) polymerase activation. Br J Pharmacol. 2002;135:1347-1350.
22. Soriano FG, Pacher P, Mabley J, et al. Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of Poly(ADP-ribose) polymerase. Circ Res. 2001; 89:684-691.
23. Zingarelli B, Cuzzocrea S, Zsengeller Z, et al. Protection against myocardial ischemia and reperfusion injury by 3-aminobenzamide, an inhibitor of Poly(ADP-ribose) synthetase. Caediovasc Res. 1997; 36:205-215.
24. Yu X, Cheng X, Xie JJ, et al. Poly (ADP-ribose) Polymerase Inhibition Improves Endothelial Dysfunction Induced by Hyperhomocysteinemia in Rats. Cardiovasc Drug Ther. 2008 Oct 24.
1. McCully KS. Homocyst (e)ine and vascular disease. Nat Med. 1996;2:386-389.
2. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991 ;324:1149-1155.
3. Duell PB, Malinow MR. Homocyst (e)ine: an important risk factor for atherosclerotic vascular disease. Curr Opin Lipidol. 1997;8:28-34.
4. Refsum H, Ueland PM, Nygard O, et al. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62.
5. Upchurch GR Jr, Welch GN, Fabian AJ, et al. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem.1997;272:17012-17017.
6. Weiss N, Heydrick S, Zhang YY, et al. Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine p-synthase-deficient mice. Arterioscler Thromb Vasc Biol. 2002;22:34-41.
7. Schlaich MP, John S, Jacobi J, et al. Mildly elevated homocysteine concentrations impair endothelium dependent vasodilation in hypercholesterolemic patients. Atherosclerosis. 2000;153: 383-389.
8. Eberhardt RT, Forgione MA, Cap A, et al. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest. 2000; 106:483-491.
9. Morita H, Kurihara H, Yoshida S, et al. Diet-induced hyperhomocysteinemia exacerbates neointima formation in rat carotid arteries after balloon injury. Circulation. 2001;103:133-139.
10. Au-Yeung KK, Woo CW, Sung FL, et al. Hyperhomocysteinemia activates nuclear factor-kappaB in endothelial cells via oxidative stress. Circ Res. 2004;94:28-36.
11.Baeuerle PA. IκB-NF-κB structures: at the interface of inflammation control. Cell. 1998;95:729-731.
12. Karin M. The beginning of the end: IκB kinase (IKK) and NF-κB activation. J Biol Chem. 1999;274:27339-27342.
13. Mercurio F, Zhu H, Murray BW, et al. IKK-1 and IKK-2: cytokine-activated IκB kinases essential for NF-κB activation. Science. 1997;278:860-866.
14. Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation.2002; 106:927-932.
15. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: The role of poly (ADP -ribose) polymerase activation. Nat Med. 2001;7:108-113.
16. Pieper AA, Walles T, Wei G, et al. Myocardial postischemic injury is reduced by poly (ADP -ribose) polymerase-1 gene disruption. Mol Med. 2006;6:271-281.
17. Sharp C, Warren A, Oshima T, et al. Poly ADP -ribose polymerase inhibitors prevent the upregulation of ICAM-1 and E-selectin in response to Th1 cytokine stimulation. Inflammation. 2001;25:157-163.
18. Hassa PO, Hottiger MO. The functional role of poly (ADP -ribose) polymerase 1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell Mol Life Sci. 2002;59:1534-1553.
19. Carrillo A, Monreal Y, Ramirez P, et al. Transcription regulation of TNF-alpha-early response genes by poly (ADP -ribose) polymerase-1 in murine heart endothelial cells.Nucleic Acids Res. 2004;32:757-766.
20. Chiarugi A, Moskowitz MA. Poly (ADP -ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J Neurochem. 2003;85:306-317.
21. Le Page C, Sanceau J, Drapier JC, et al. Inhibition of ADP -ribosylation impair inducible nitric oxide synthase gene transcription through inhibition of NF kappa B activation. Biochem Biophys Res Commum. 1998;243:451-457.
22. Oliver FJ, Menissier-de Murcia J, Nacci C, et al. Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP -ribose) polymerase-1deficentmice. EMBO J. 1999;18:4446-4454.
23. Zhou J, Werstuck GH, Lhotak S, et al. Hyperhomocysteinemia induced by methionine supplementation dose not independently cause atherosclerosis in C57BL/6J mice. FASEB. 2008;22:2569-78.
24. Zhou J, Mφller J, Danielsen CC, et al. Dietary supplementation with menthionine and homocysteine promotes early athrosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2001;21:1470-1476.
25. Zhou J, Mφller J, Ritskes-Hoitinga M, et al. Effect of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice. Atheroscletosis. 2003;168:255-262.
26. Wang H, Jiang X, Yang F, et al. Hyperhomocysteinemia accelerates atherosclerosis in cystathiorine betasynthase and apolipoprotein E double knock-out mice with and without dietary pertyrbation. Blood. 2003;101:3901-3907.
27. Hofmann MA, Lalla E, Lu Y, et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001;107:675-683.
28. Werns SW, Walton JA, Hsia HH, et al. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation. 1989;79:287-291.
29. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Chin Invest, 1986;77:1370-1376.
30. Szabo C, Dawson VL. Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci. 1998; 19:287-298.
31. Pieper AA, Brat DJ, Krug DK, et al. Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. Proc Natl Acad Sci USA. 1999;96:3059-3064.
32. Yu X, Cheng X, Xie JJ, et al. Poly (ADP-ribose) Polymerase Inhibition Improves Endothelial Dysfunction Induced by Hyperhomocysteinemia in Rats. Cardiovasc Drug Ther. 2008 Oct 24.
33. Shishodia S, Aggarwal BB. Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. J Biol Chem. 2004;279(45):47148-58.
34. D' Amours D, Desnoyers S, D' Silva I, et al. Poly (ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J. 1999;342:249-268.
35. Chiarugi A. Poly (ADP-ribose) polymerase: killer or conspirator? The 'suicide hypothesis' revisited. Trends Pharmacol Sci. 2002;23:122-129.
36. Hassa PO, Covic M, Hasan S, et al. The enzymatic and DNA binding activity of PARP-1 are not required for NF-κB coactivator function. J Biol Chem.2001;276:45588-45597.
37. Oumouna-Benachour K, Hans CP, Suzuki Y, et al. Poly(ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death. Circulation.2007;115(8):2442-50.
38. Schraufstatter IU, Hyslop PA, Hinshaw DB, et al. Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly (ADP-ribose) polymerase. Proc Natl Acad Sci U S A. 1986;83:4908-4912.
39. Szabo C, Zingarelli B, O'Connor M, et al. DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proc Natl Acad Sci U S A. 1996;93:1753-1758.
1. Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995; 274:1049-1057.
2. Harrison DG, Cai H, Landmesser U, et al. Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2003; 4:51-61.
3. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: The role of poly (ADP -ribose) polymerase activation. Nat Med. 2001; 7:108-113.
4. Pieper AA, Walles T, Wei G, et al. Myocardial postischemic injury is reduced by poly (ADP -ribose) polymerase-1 gene disruption. Mol Med. 2006; 6:271-281.
5. Tawakol A, Omland T, Gerhard M, et al. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation. 1997;95:1119-1121.
6. Lang D, Kredan MB, Moat SJ, et al. Homocysteine-induced inhibition of endothelium-dependent relaxation in rabbit aorta: Role for superoxide anions.Arterioscler Thromb Vasc Biol. 2000;20:422-427.
7. McDowell IF, Lang D. Homocysteine and endothelial dysfunction: A link with cardiovascular disease. J Nutr. 2000;130(2S suppl):369S-372S.
8. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: The role of poly (ADP -ribose) polymerase activation. Nat Med. 2001;7:108-113.
9. Pieper AA, Walles T, Wei G, et al. Myocardial postischemic injury is reduced by poly (ADP -ribose) polymerase-1 gene disruption. Mol Med. 2006;6:271-281.
10. Hassa PO, Hottiger MO. The functional role of poly (ADP -ribose) polymerase 1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell Mol Life Sci. 2002;59:1534-1553.
11.Chiarugi A, Moskowitz MA. Poly (ADP -ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J Neurochem. 2003;85:306-317.
12. Le Page C, Sanceau J, Drapier JC, et al. Inhibition of ADP -ribosylation impair inducible nitric oxide synthase gene transcription through inhibition of NF kappa B activation. Biochem Biophys Res Commum. 1998;243:451-457.
13. Oliver FJ, Menissier-de Murcia J, Nacci C, et al. Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP -ribose) polymerase-1deficent mice. EMBO J. 1999; 18:4446-4454.
14. Gutierrez SH, Kuri MR, del Castillo ER. Cardiac role of the transcription factor NF-kappa B. Cardiavasc Hematol Disord Drug Targets.2008;8:153-60.
15. Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation.2002;106:927-932.
16. Zingarellli B, Hake PW, O'Connor M, et al. Absence of Poly (ADP-ribose)polymerase-1 alters nuclear factor-kappa B activation and gene expression of apoptosis regulators after reperfusion injury. Mol Med. 2003;9:143-153.
17. Huang RFS, Huang SM, Lin BS, et al. Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells. Life Sci. 2001;68:2799-2811.
18. Karaflou M, Lambrinoudaki I, Christodoulakos G. Apoptosis in atherosclerosis: a mini-review. Mini Rev Med Chem.2008;8:912-8.
19. Zhou J, Werstuck GH, Lhotak S, et al. Hyperhomocysteinemia induced by methionine supplementation dose not independently cause atherosclerosis in C57BL/6J mice.FASEB. 2008;22:2569-78.
20. Joshi SG, Francis CW, Silverman DJ, et al. Nuclear factor kappa B protects against host cell apoptosis during Rickettsia rickettsii infection by inhibiting activation of apical and effector caspases and maintaining mitochondrial integrity. Infect Immun. 2003;71(7):4127-36.
21. Zhou J, Mφller J, Danielsen CC, ea al. Dietary supplementation with menthionine and homocysteine promotes early athrosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2001;21:1470-1476.
22. Zhou J, Mφller J, Ritskes-Hoitinga M, et al. Effect of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice. Atheroscletosis.2003; 168:255-262.
23. Wang H, Jiang X, Yang F, et al. Hyperhomocysteinemia accelerates atherosclerosis in cystathiorine betasynthase and apolipoprotein E double knock-out mice with and without dietary pertyrbation. Blood. 2003; 101:3901 -3907.
24. Hofmann MA, Lalla E, Lu Y, et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001; 107:675-683.
25. Werns SW, Walton JA, Hsia HH, et al. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation. 1989;79:287-291.
26. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Chin Invest. 1986;77:1370-1376.
27. Szabo C, Dawson VL. Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci. 1998; 19:287-298.
28. Au-Yeung KK, Woo CW, Sung FL, et al. Hyperhomocysteinemia activates nuclear factor-kappaB in endothelial cells via oxidative stress. Circ Res. 2004;94:28-36.
29. Hassa PO, Covic M, Hasan S, et al. The enzymatic and DNA binding activity of PARP-1 are not required for NF-κB coactivator function. J Biol Chem. 2001 ;276:45588-45597.
30. Oumouna-Benachour K, Hans CP, Suzuki Y, et al. Poly(ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death. Circulation. 2007;115(8):2 442-50.
31. Lazebnik YA, Kaufmann SH, Desnoyers S, et al. Cleavage of PoIy(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature. 1994;371:346-347.
32. Isner JM, Kearney M, Bortman S, et al. Apoptosis in human atherosclerosis and restenosis. Circulation. 1995;91:2703-2711.
33. Kockx MM, De Meyer GR, Muhring J, et al. Distribution of cell replication and apoptosis in atherosclerotic plaques of cholesterol-fed rabbits. Atherosclerosis. 1996;120:115-124.
34. Hegyi L, Skepper JN, Cary NR, et al. Foam cell apoptosis and the development of the lipid core of human atherosclerosis. J Pathol.l996;180:423-442.
35. Litttlewood TD, Bennett MR: Apoptotic cell death in atherosclerosis. Curr Opin Lipidol. 2003;14:469-475.
1. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1996;340:115-126.
2. Grainger DJ, Metcalfe JC. A pivotal role for TGF-beta in atherogenesis? Biol Rev Camb Philos Soc. 1995;70:571-96.
3. Hansson GK, Robertson AK. TGF-beta in atherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24:E137 [author reply E-8].
4. Mallat Z, Tedgui A. The role of transforming growth factor beta in atherosclerosis: novel insights and future perspectives. Curr Opin Lipidol. 2002; 13:523-9.
5. Singh NN, Ramji DP. The role of transforming growth factor-beta in atherosclerosis. Cytokine Growth Factor Rev. 2006
6. Engelse MA, Neele JM, van Achterberg TA, et al. Human activin-A is expressed in the atherosclerotic lesion and promotes the contractile phenotype of smooth muscle cells. Circ Res. 1999;85:931-939.
7. Dhore CR, Cleutjens JP, Lutgens E, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol.2001;21:1998-2003.
8. Willette RN, Gu JL, Lysko PG, et al. BMP-2 gene expression and effects on human vascular smooth muscle cells. J Vasc Res. 1999;36:120-125.
9. Ignotz RA, Endo T, Massague J. Regulation of fibronectin and type Ⅰcollagen mRNA levels by transforming growth factor-beta. J Biol Chem. 1987;262:6443-6.
10. Penttinen RP, Kobayashi S, Bornstein P. Transforming growth factor beta increases mRNA for matrix proteins both in the presence and in the absence of changes in mRNA stability. Proc Natl Acad Sci U S A. 1988;85:1105-8.
11. Grainger DJ, Kemp PR, Witchell CM, et al, Metcalfe JC. Transforming growth factor beta decreases the rate of proliferation of rat vascular smooth muscle cells by extending the G2 phase of the cell cycle and delays the rise in cyclic AMP before entry into M phase. Biochem J. 1994;299(Pt 1):227-35.
12. Owens GK, Geisterfer AA, Yang YW, et al. Transforming growth factor-beta-induced growth inhibition and cellular hypertrophy in cultured vascular smooth muscle cells. J Cell Biol. 1988;107:771-80.
13. Bjorkerud S. Effects of transforming growth factor-beta 1 on human arterial smooth muscle cells in vitro. Arterioscler Thromb. 1991 ;11:892-902.
14. Gamble JR, Khew-Goodall Y, Vadas MA. Transforming growth factor-beta inhibits E-selectin expression on human endothelial cells. J Immunol. 1993;150:4494-503.
15. Argmann CA, Van Den Diepstraten CH, Sawyez CG, et al. Transforming growth factor-betal inhibits macrophage cholesteryl ester accumulation induced by native and oxidized VLDL remnants. Arterioscler Thromb Vasc Biol. 2001;21:2011-8.
16. Grainger DJ, Mosedale DE, Metcalfe JC, et al. Dietary fat and reduced levels of TGFbetal act synergistically to promote activation of the vascular endothelium and formation of lipid lesions. J Cell Sci. 2000;113(Pt 13):2355-61.
17. Mallat Z, Gojova A, Marchiol-Fournigault C, et al. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res. 2001;89:930-4.
18. Grainger DJ, Kemp PR, Metcalfe JC, et al. The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis. Nat Med. 1995;1:74-9.
19. WangXL, Liu SX,WilckenDE. Circulating transforming growth factor beta 1 and coronary artery disease. Cardiovasc Res. 1997;34:404-10.
20. Jiang X, Zeng HS, Guo Y, et al. The expression of matrix metalloproteinases-9, transforming growth factor-betal and transforming growth factor-beta receptor Ⅰ in human atherosclerotic plaque and their relationship with plaque stability. Chin Med J (Engl). 2004; 117:1825-9.
21. Bobik A, Agrotis A, Kanellakis P, et al. Distinct patterns of transforming growth factor-beta isoform and receptor expression in human atherosclerotic lesions. Colocalization implicates TGF-beta in fibrofatty lesion development. Circulation. 1999;99:2883-91.
22. Piao M, Tokunaga O. Significant expression of endoglin (CD105), TGFbeta-1 and TGFbeta R-2 in the atherosclerotic aorta: an immunohistological study. J Atheroscler Thromb. 2006; 13:82-9.
23. Grainger DJ, Heathcote K, Chiano M, et al. Genetic control of the circulating concentration of transforming growth factor type betal. Hum Mol Genet. 1999;8:93-7.
24. Silverman ES, Palmer LJ, Subramaniam V, et al. Transforming growth factor-beta 1 promoter polymorphism C-509T is associated with asthma. Am J Respir Crit Care Med.2004;169:214-9.
25. Luedecking EK, DeKosky ST, Mehdi H, et al. Analysis of genetic polymorphisms in the transforming growth factorbetal gene and the risk of Alzheimer's disease. Hum Genet. 2000;106:565-9.
26. Awad MR, El-Gamel A, Hasleton P, et al. Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation. 1998;66:1014-20.
27. Suthanthiran M, Li B, Song JO,DingR, et al. Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: a novelmediator of hypertension and/or target organ damage. Proc Natl Acad Sci U S A. 2000;97:3479-84.
28. Yamada Y, Miyauchi A, Goto J, et al. Association of a polymorphism of the transforming growth factorbetal gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J Bone Miner Res. 1998; 13:1569-76.
29. Yokota M, Ichihara S, Lin TL, et al. Association of a T29-NC polymorphism of the transforming growth factor-betal gene with genetic susceptibility to myocardial infarction in Japanese. Circulation. 2000; 101:2783-7.
30. Cambien F, Ricard S, Troesch A,Mallet C, et al. Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de l'Infarctus du Myocarde (ECTIM) Study. Hypertension.1996;28:881-7.
31. Tang B, Bottinger EP, Jakowlew SB, et al. Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency. Nat Med. 1998;4:802-7.
32. Lutgens E, Gijbels M, Smook M, et al. Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. Arterioscler Thromb Vasc Biol. 2002;22:975-82.
33. Gojova A, Brun V, Esposito B, et al. Specific abrogation of transforming growth factor-{beta} signaling in T cells alters atherosclerotic lesion size and composition in mice. Blood. 2003.
34. Robertson AK, Rudling M, Zhou X, et al. Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest. 2003;112:1342-50.
35. ten Dijke P, Hill CS. New insights into TGF-beta-Smad signalling. Trends Biochem Sci. 2004;29:265-73.
36. McCaffrey TA, Consigli S, Du B, et al. Decreased type Ⅱ/type I TGF-βreceptor ratio in cells derived from human atherosclerotic lesions. Conversion from an antiproliferative to profibrotic response to TGF-β . J Clin Invest. 1995;96:2667-2675.
37. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685-700.
38. Moustakas A, Heldin CH. Non-Smad TGF-beta signals. J Cell Sci. 2005;118:3573-84.
39. McCaffrey TA, Du B, Consigli S, et al. Genomic instability in the type Ⅱ TGF-beta1 receptor gene in atherosclerotic and restenotic vascular cells. J Clin Invest. 1997; 100:2182-8.
40. Evanko SP, Raines EW, Ross R, et al. Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics, and the proximity of platelet-derived growth factor and transforming growth factor-beta. Am J Pathol.1998;152: 533-46.
41. Li CG, Bethell H, Wilson PB, et al. The significance of CD105, TGFbeta and CD105/TGFbeta complexes in coronary artery disease. Atherosclerosis. 2000; 152:249-56.
42. Kalinina N, Agrotis A, Antropova Y, et al. Smad expression in human atherosclerotic lesions: evidence for impaired TGF-beta/Smad signaling in smooth muscle cells of fibrofatty lesions. Arterioscler Thromb Vasc Biol. 2004;24:1391-6.
43. Oshima M, Oshima H, Taketo MM. TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol. 1996; 179:297-302.
44. Disabella E, Grasso M, Marziliano N, et al. Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects. Eur J Hum Genet. 2006; 14:34-8.
45. Singh KK, Rommel K, Mishra A, et al. TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat.2006;27:770-7.
46. Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352:337-9.
47. Lee B, Godfrey M, Vitale E, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature. 1991;352:330-4.
48. Maslen CL, Corson GM, Maddox BK, et al. Partial sequence of a candidate gene for the Marfan syndrome. Nature. 1991;352:334-7.
49. Saharinen J, Hyytiainen M, Taipale J, et al. Latent transforming growth factor-beta binding proteins (LTBPs)-structural extracellular matrix proteins for targeting TGF-beta action. Cytokine Growth Factor Rev. 1999; 10:99-117.
50. Veillard NR, Steffens S, Burger F, et al. Differential expression patterns of proinflammatory and antiinflammatory mediators during atherogenesis in mice. Arterioscler Thromb Vasc Biol. 2004;24: 2339-2344.
51. Ait-Oufella H, Salomon BL, Potteaux S, et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med. 2006; 12:178 -180.
52. Fahlen L, Read S, Gorlik L, et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J Exp Med. 2005;201:737-746.
53. Marie JC, Letterio JJ, Gavin M, et al. TGF- β 1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med. 2005;201:1061-1067.
54. Li D, Liu Y, Chen J, et al. Suppression of atherogenesis by delivery of TGFbeta 1ACT using adeno-associated virus type 2 in LDLR knockout mice. Biochem Biophys Res Commun. 2006;344:701-7.
55. Koglin J, Glysing-Jensen T, Raisanen-Sokolowski A, et al. Immune sources of transforming growth factor-beta1 reduce transplant arteriosclerosis: insight derived from a knockout mouse model. Circ Res. 1998;83:652-60.
56. Nabel EG, Shum L, Pompili VJ, et al. Direct transfer of transforming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia. Proc Natl Acad Sci U S A.1993;90:10759-63.
57. Grainger DJ, Weissberg PL, Metcalfe JC. Tamoxifen decreases the rate of proliferation of rat vascular smooth-muscle cells in culture by inducing production of transforming growth factor beta. Biochem J. 1993;294(Pt 1):109-12.
58. Grainger DJ, Kirschenlohr HL, Metcalfe JC, et al. Proliferation of human smooth muscle cells promoted by lipoprotein(a). Science. 1993;260:1655-8.
59. Clarke SC, Schofield PM, Grace AA, et al. Tamoxifen effects on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis. Circulation.2001; 103:1497-502.
60. Grainger DJ. Transforming growth factor beta and atherosclerosis: so far, so good for the protective cytokine hypothesis. Arterioscler Thromb Vasc Biol. 2004;24:399-404.
61. Grainger DJ, Schofield PM. Tamoxifen for the prevention of myocardial infarction in humans: preclinical and early clinical evidence. Circulation. 2005; 112:3018-24.
2. Tawakol A, Omland T, Gerhard M, et al. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation.1997;95:1119-1121.
3. Lang D, Kredan MB, Moat SJ, et al. Homocysteine-induced inhibition of endothelium-dependent relaxation in rabbit aorta: Role for superoxide anions.Arterioscler Thromb Vasc Biol. 2000;20:422-427.
4. McDowell IF, Lang D. Homocysteine and endothelial dysfunction: A link with cardiovascular disease. J Nutr. 2000;130(2S suppl):369S-372S.
5. Harrison DG, Cai H, Landmesser U, et al. Interactions of angiotensin Ⅱ with NAD(P)H oxidase, oxidant stress and cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2003;4:51-61.
6. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315-424.
7. Rubbo H, O'Donnell V. Nitric oxide, peroxynitrite and lipoxygenase in atherogenesis: Mechanistic insights. Toxicology. 2005;208:305-317.
8. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: The role of poly (ADP -ribose) polymerase activation. Nat Med. 2001;7:108-113.
9. Pieper AA, Walles T, Wei G, et al. Myocardial postischemic injury is reduced by poly (ADP -ribose) polymerase-1 gene disruption. Mol Med. 2006;6:271-281.
10. Sharp C, Warren A, Oshima T, et al. Poly ADP -ribose polymerase inhibitors prevent the upregulation of ICAM-1 and E-selectin in response to Th1 cytokine stimulation. Inflammation. 2001;25:157-163.
11. Hassa PO, Hottiger MO. The functional role of poly (ADP -ribose) polymerase 1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell Mol Life Sci. 2002;59:1534-1553.
12. Carrillo A, Monreal Y, Ramirez P, et al. Transcription regulation of TNF-alpha-early response genes by poly (ADP -ribose) polymerase-1 in murine heart endothelial cells. Nucleic Acids Res. 2004;32:757-766.
13. Chiarugi A, Moskowitz MA. Poly (ADP -ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J Neurochem. 2003;85:306-317.
14. Le Page C, Sanceau J, Drapier JC, et al. Inhibition of ADP -ribosylation impair inducible nitric oxide synthase gene transcription through inhibition of NF kappa B activation. Biochem Biophys Res Commum. 1998;243:451-457.
15. Oliver FJ, Menissier-de Murcia J, Nacci C, et al. Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP -ribose) polymerase-1deficent mice. EMBO J. 1999;18:4446-4454.
16. Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation. 2002;106:927-932.
17. Oumouna-Benachour K, Hans CP, Suzuki Y, et al. Poly(ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death. Circulation. 2007;115(8):2442-50.
18. Zingarellli B, Hake PW, O'Connor M, et al. Absence of Poly(ADP-ribose) polymerase-1 alters nuclear factor-kappa B activation and gene expression of apoptosis regulators after reperfusion injury. Mol Med. 2003;9:143-153.
1. Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995; 274:1049-1057.
2. Harrison DG, Cai H, Landmesser U, et al. Interactions of angiotensin Ⅱ with NAD(P)H oxidase, oxidant stress and cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2003; 4:51-61.
3. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: The role of poly (ADP -ribose) polymerase activation. Nat Med. 2001; 7:108-113.
4. Pieper AA, Walles T, Wei G, et al. Myocardial postischemic injury is reduced by poly (ADP -ribose) polymerase-1 gene disruption. Mol Med. 2006; 6:271-281.
5. Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation. 2002;106:927-932.
6. Inoue S, Egashira K, Ni W, et al. Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein E-knockout mice. Circulation. 2002; 106:2700-2706.
7. Paigen B, Morrow A, Holmes PA, et al. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis. 1987;68:231-240.
8. Cheng X, Chen Y, Xie JJ, et al. Suppressive oligodeoxynucleotides inhibit atherosclerosis in ApoE (-/-) mice through modulation of Th1/Th2 balance. J Mol Cell Cardiol. 2008;45(2): 168-75.
9. Ni W, Egashira K, Kitamoto S, et al. New Anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice. Circulation.2001; 103:2096-2101.
10. Siow YL, Au-Yeung KK, Woo CW, et al. Homocysteine stimulates phosphorylation of NAPDH oxidase p47phox and p67phox subunits in monocytes via protein kinase Cbeta activation. Biochem J. 2006;398(1):73-82.
11. Tasatargil A, Dalaklioglu S, Sadan G. Poly (ADP-ribose) polymerase inhibition prevents homocysteine-induced endothelial dysfunction in the isolated rat aorta. Pharmacology. 2004;72(2):99-105.
12. Zhou J, Mφller J, Danielsen CC, et al. Dietary supplementation with menthionine and homocysteine promotes early athrosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2001 ;21:1470-1476.
13. Zhou J, Mφller J, Ritskes-Hoitinga M, et al. Effect of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice. Atheroscletosis. 2003;168:255-262.
14. Wang H, Jiang X, Yang F, et al. Hyperhomocysteinemia accelerates atherosclerosis in cystathiorine betasynthase and apolipoprotein E double knock-out mice with and without dietary pertyrbation. Blood. 2003;101:3901-3907.
15. Hofmann MA, Lalla E, Lu Y, et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001;107:675-683.
16. Oumouna-Benachour K, Hans CP, Suzuki Y, et al. Poly (ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death. Circulation. 2007; 115(8):2442-50.
17. Werns SW, Walton JA, Hsia HH, et al. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation. 1989;79:287-291.
18. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Chin Invest. 1986;77:1370-1376.
19. Szabo C, Dawson VL. Role of poly (ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci. 1998;19:287-298.
20. Pieper AA, Brat DJ, Krug DK, et al. Poly (ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. Proc Natl Acad Sci USA. 1999;96:3059-3064.
21. Pacher P, Mabley JG, Soriano FG, et al. Endothelial dysfunction in aging animals: The role of Poly(ADP-ribose) polymerase activation. Br J Pharmacol. 2002;135:1347-1350.
22. Soriano FG, Pacher P, Mabley J, et al. Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of Poly(ADP-ribose) polymerase. Circ Res. 2001; 89:684-691.
23. Zingarelli B, Cuzzocrea S, Zsengeller Z, et al. Protection against myocardial ischemia and reperfusion injury by 3-aminobenzamide, an inhibitor of Poly(ADP-ribose) synthetase. Caediovasc Res. 1997; 36:205-215.
24. Yu X, Cheng X, Xie JJ, et al. Poly (ADP-ribose) Polymerase Inhibition Improves Endothelial Dysfunction Induced by Hyperhomocysteinemia in Rats. Cardiovasc Drug Ther. 2008 Oct 24.
1. McCully KS. Homocyst (e)ine and vascular disease. Nat Med. 1996;2:386-389.
2. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991 ;324:1149-1155.
3. Duell PB, Malinow MR. Homocyst (e)ine: an important risk factor for atherosclerotic vascular disease. Curr Opin Lipidol. 1997;8:28-34.
4. Refsum H, Ueland PM, Nygard O, et al. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62.
5. Upchurch GR Jr, Welch GN, Fabian AJ, et al. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem.1997;272:17012-17017.
6. Weiss N, Heydrick S, Zhang YY, et al. Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine p-synthase-deficient mice. Arterioscler Thromb Vasc Biol. 2002;22:34-41.
7. Schlaich MP, John S, Jacobi J, et al. Mildly elevated homocysteine concentrations impair endothelium dependent vasodilation in hypercholesterolemic patients. Atherosclerosis. 2000;153: 383-389.
8. Eberhardt RT, Forgione MA, Cap A, et al. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest. 2000; 106:483-491.
9. Morita H, Kurihara H, Yoshida S, et al. Diet-induced hyperhomocysteinemia exacerbates neointima formation in rat carotid arteries after balloon injury. Circulation. 2001;103:133-139.
10. Au-Yeung KK, Woo CW, Sung FL, et al. Hyperhomocysteinemia activates nuclear factor-kappaB in endothelial cells via oxidative stress. Circ Res. 2004;94:28-36.
11.Baeuerle PA. IκB-NF-κB structures: at the interface of inflammation control. Cell. 1998;95:729-731.
12. Karin M. The beginning of the end: IκB kinase (IKK) and NF-κB activation. J Biol Chem. 1999;274:27339-27342.
13. Mercurio F, Zhu H, Murray BW, et al. IKK-1 and IKK-2: cytokine-activated IκB kinases essential for NF-κB activation. Science. 1997;278:860-866.
14. Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation.2002; 106:927-932.
15. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: The role of poly (ADP -ribose) polymerase activation. Nat Med. 2001;7:108-113.
16. Pieper AA, Walles T, Wei G, et al. Myocardial postischemic injury is reduced by poly (ADP -ribose) polymerase-1 gene disruption. Mol Med. 2006;6:271-281.
17. Sharp C, Warren A, Oshima T, et al. Poly ADP -ribose polymerase inhibitors prevent the upregulation of ICAM-1 and E-selectin in response to Th1 cytokine stimulation. Inflammation. 2001;25:157-163.
18. Hassa PO, Hottiger MO. The functional role of poly (ADP -ribose) polymerase 1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell Mol Life Sci. 2002;59:1534-1553.
19. Carrillo A, Monreal Y, Ramirez P, et al. Transcription regulation of TNF-alpha-early response genes by poly (ADP -ribose) polymerase-1 in murine heart endothelial cells.Nucleic Acids Res. 2004;32:757-766.
20. Chiarugi A, Moskowitz MA. Poly (ADP -ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J Neurochem. 2003;85:306-317.
21. Le Page C, Sanceau J, Drapier JC, et al. Inhibition of ADP -ribosylation impair inducible nitric oxide synthase gene transcription through inhibition of NF kappa B activation. Biochem Biophys Res Commum. 1998;243:451-457.
22. Oliver FJ, Menissier-de Murcia J, Nacci C, et al. Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP -ribose) polymerase-1deficentmice. EMBO J. 1999;18:4446-4454.
23. Zhou J, Werstuck GH, Lhotak S, et al. Hyperhomocysteinemia induced by methionine supplementation dose not independently cause atherosclerosis in C57BL/6J mice. FASEB. 2008;22:2569-78.
24. Zhou J, Mφller J, Danielsen CC, et al. Dietary supplementation with menthionine and homocysteine promotes early athrosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2001;21:1470-1476.
25. Zhou J, Mφller J, Ritskes-Hoitinga M, et al. Effect of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice. Atheroscletosis. 2003;168:255-262.
26. Wang H, Jiang X, Yang F, et al. Hyperhomocysteinemia accelerates atherosclerosis in cystathiorine betasynthase and apolipoprotein E double knock-out mice with and without dietary pertyrbation. Blood. 2003;101:3901-3907.
27. Hofmann MA, Lalla E, Lu Y, et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001;107:675-683.
28. Werns SW, Walton JA, Hsia HH, et al. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation. 1989;79:287-291.
29. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Chin Invest, 1986;77:1370-1376.
30. Szabo C, Dawson VL. Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci. 1998; 19:287-298.
31. Pieper AA, Brat DJ, Krug DK, et al. Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. Proc Natl Acad Sci USA. 1999;96:3059-3064.
32. Yu X, Cheng X, Xie JJ, et al. Poly (ADP-ribose) Polymerase Inhibition Improves Endothelial Dysfunction Induced by Hyperhomocysteinemia in Rats. Cardiovasc Drug Ther. 2008 Oct 24.
33. Shishodia S, Aggarwal BB. Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. J Biol Chem. 2004;279(45):47148-58.
34. D' Amours D, Desnoyers S, D' Silva I, et al. Poly (ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J. 1999;342:249-268.
35. Chiarugi A. Poly (ADP-ribose) polymerase: killer or conspirator? The 'suicide hypothesis' revisited. Trends Pharmacol Sci. 2002;23:122-129.
36. Hassa PO, Covic M, Hasan S, et al. The enzymatic and DNA binding activity of PARP-1 are not required for NF-κB coactivator function. J Biol Chem.2001;276:45588-45597.
37. Oumouna-Benachour K, Hans CP, Suzuki Y, et al. Poly(ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death. Circulation.2007;115(8):2442-50.
38. Schraufstatter IU, Hyslop PA, Hinshaw DB, et al. Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly (ADP-ribose) polymerase. Proc Natl Acad Sci U S A. 1986;83:4908-4912.
39. Szabo C, Zingarelli B, O'Connor M, et al. DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proc Natl Acad Sci U S A. 1996;93:1753-1758.
1. Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995; 274:1049-1057.
2. Harrison DG, Cai H, Landmesser U, et al. Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2003; 4:51-61.
3. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: The role of poly (ADP -ribose) polymerase activation. Nat Med. 2001; 7:108-113.
4. Pieper AA, Walles T, Wei G, et al. Myocardial postischemic injury is reduced by poly (ADP -ribose) polymerase-1 gene disruption. Mol Med. 2006; 6:271-281.
5. Tawakol A, Omland T, Gerhard M, et al. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation. 1997;95:1119-1121.
6. Lang D, Kredan MB, Moat SJ, et al. Homocysteine-induced inhibition of endothelium-dependent relaxation in rabbit aorta: Role for superoxide anions.Arterioscler Thromb Vasc Biol. 2000;20:422-427.
7. McDowell IF, Lang D. Homocysteine and endothelial dysfunction: A link with cardiovascular disease. J Nutr. 2000;130(2S suppl):369S-372S.
8. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: The role of poly (ADP -ribose) polymerase activation. Nat Med. 2001;7:108-113.
9. Pieper AA, Walles T, Wei G, et al. Myocardial postischemic injury is reduced by poly (ADP -ribose) polymerase-1 gene disruption. Mol Med. 2006;6:271-281.
10. Hassa PO, Hottiger MO. The functional role of poly (ADP -ribose) polymerase 1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell Mol Life Sci. 2002;59:1534-1553.
11.Chiarugi A, Moskowitz MA. Poly (ADP -ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J Neurochem. 2003;85:306-317.
12. Le Page C, Sanceau J, Drapier JC, et al. Inhibition of ADP -ribosylation impair inducible nitric oxide synthase gene transcription through inhibition of NF kappa B activation. Biochem Biophys Res Commum. 1998;243:451-457.
13. Oliver FJ, Menissier-de Murcia J, Nacci C, et al. Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP -ribose) polymerase-1deficent mice. EMBO J. 1999; 18:4446-4454.
14. Gutierrez SH, Kuri MR, del Castillo ER. Cardiac role of the transcription factor NF-kappa B. Cardiavasc Hematol Disord Drug Targets.2008;8:153-60.
15. Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation.2002;106:927-932.
16. Zingarellli B, Hake PW, O'Connor M, et al. Absence of Poly (ADP-ribose)polymerase-1 alters nuclear factor-kappa B activation and gene expression of apoptosis regulators after reperfusion injury. Mol Med. 2003;9:143-153.
17. Huang RFS, Huang SM, Lin BS, et al. Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells. Life Sci. 2001;68:2799-2811.
18. Karaflou M, Lambrinoudaki I, Christodoulakos G. Apoptosis in atherosclerosis: a mini-review. Mini Rev Med Chem.2008;8:912-8.
19. Zhou J, Werstuck GH, Lhotak S, et al. Hyperhomocysteinemia induced by methionine supplementation dose not independently cause atherosclerosis in C57BL/6J mice.FASEB. 2008;22:2569-78.
20. Joshi SG, Francis CW, Silverman DJ, et al. Nuclear factor kappa B protects against host cell apoptosis during Rickettsia rickettsii infection by inhibiting activation of apical and effector caspases and maintaining mitochondrial integrity. Infect Immun. 2003;71(7):4127-36.
21. Zhou J, Mφller J, Danielsen CC, ea al. Dietary supplementation with menthionine and homocysteine promotes early athrosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2001;21:1470-1476.
22. Zhou J, Mφller J, Ritskes-Hoitinga M, et al. Effect of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice. Atheroscletosis.2003; 168:255-262.
23. Wang H, Jiang X, Yang F, et al. Hyperhomocysteinemia accelerates atherosclerosis in cystathiorine betasynthase and apolipoprotein E double knock-out mice with and without dietary pertyrbation. Blood. 2003; 101:3901 -3907.
24. Hofmann MA, Lalla E, Lu Y, et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001; 107:675-683.
25. Werns SW, Walton JA, Hsia HH, et al. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation. 1989;79:287-291.
26. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Chin Invest. 1986;77:1370-1376.
27. Szabo C, Dawson VL. Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci. 1998; 19:287-298.
28. Au-Yeung KK, Woo CW, Sung FL, et al. Hyperhomocysteinemia activates nuclear factor-kappaB in endothelial cells via oxidative stress. Circ Res. 2004;94:28-36.
29. Hassa PO, Covic M, Hasan S, et al. The enzymatic and DNA binding activity of PARP-1 are not required for NF-κB coactivator function. J Biol Chem. 2001 ;276:45588-45597.
30. Oumouna-Benachour K, Hans CP, Suzuki Y, et al. Poly(ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death. Circulation. 2007;115(8):2 442-50.
31. Lazebnik YA, Kaufmann SH, Desnoyers S, et al. Cleavage of PoIy(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature. 1994;371:346-347.
32. Isner JM, Kearney M, Bortman S, et al. Apoptosis in human atherosclerosis and restenosis. Circulation. 1995;91:2703-2711.
33. Kockx MM, De Meyer GR, Muhring J, et al. Distribution of cell replication and apoptosis in atherosclerotic plaques of cholesterol-fed rabbits. Atherosclerosis. 1996;120:115-124.
34. Hegyi L, Skepper JN, Cary NR, et al. Foam cell apoptosis and the development of the lipid core of human atherosclerosis. J Pathol.l996;180:423-442.
35. Litttlewood TD, Bennett MR: Apoptotic cell death in atherosclerosis. Curr Opin Lipidol. 2003;14:469-475.
1. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1996;340:115-126.
2. Grainger DJ, Metcalfe JC. A pivotal role for TGF-beta in atherogenesis? Biol Rev Camb Philos Soc. 1995;70:571-96.
3. Hansson GK, Robertson AK. TGF-beta in atherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24:E137 [author reply E-8].
4. Mallat Z, Tedgui A. The role of transforming growth factor beta in atherosclerosis: novel insights and future perspectives. Curr Opin Lipidol. 2002; 13:523-9.
5. Singh NN, Ramji DP. The role of transforming growth factor-beta in atherosclerosis. Cytokine Growth Factor Rev. 2006
6. Engelse MA, Neele JM, van Achterberg TA, et al. Human activin-A is expressed in the atherosclerotic lesion and promotes the contractile phenotype of smooth muscle cells. Circ Res. 1999;85:931-939.
7. Dhore CR, Cleutjens JP, Lutgens E, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol.2001;21:1998-2003.
8. Willette RN, Gu JL, Lysko PG, et al. BMP-2 gene expression and effects on human vascular smooth muscle cells. J Vasc Res. 1999;36:120-125.
9. Ignotz RA, Endo T, Massague J. Regulation of fibronectin and type Ⅰcollagen mRNA levels by transforming growth factor-beta. J Biol Chem. 1987;262:6443-6.
10. Penttinen RP, Kobayashi S, Bornstein P. Transforming growth factor beta increases mRNA for matrix proteins both in the presence and in the absence of changes in mRNA stability. Proc Natl Acad Sci U S A. 1988;85:1105-8.
11. Grainger DJ, Kemp PR, Witchell CM, et al, Metcalfe JC. Transforming growth factor beta decreases the rate of proliferation of rat vascular smooth muscle cells by extending the G2 phase of the cell cycle and delays the rise in cyclic AMP before entry into M phase. Biochem J. 1994;299(Pt 1):227-35.
12. Owens GK, Geisterfer AA, Yang YW, et al. Transforming growth factor-beta-induced growth inhibition and cellular hypertrophy in cultured vascular smooth muscle cells. J Cell Biol. 1988;107:771-80.
13. Bjorkerud S. Effects of transforming growth factor-beta 1 on human arterial smooth muscle cells in vitro. Arterioscler Thromb. 1991 ;11:892-902.
14. Gamble JR, Khew-Goodall Y, Vadas MA. Transforming growth factor-beta inhibits E-selectin expression on human endothelial cells. J Immunol. 1993;150:4494-503.
15. Argmann CA, Van Den Diepstraten CH, Sawyez CG, et al. Transforming growth factor-betal inhibits macrophage cholesteryl ester accumulation induced by native and oxidized VLDL remnants. Arterioscler Thromb Vasc Biol. 2001;21:2011-8.
16. Grainger DJ, Mosedale DE, Metcalfe JC, et al. Dietary fat and reduced levels of TGFbetal act synergistically to promote activation of the vascular endothelium and formation of lipid lesions. J Cell Sci. 2000;113(Pt 13):2355-61.
17. Mallat Z, Gojova A, Marchiol-Fournigault C, et al. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res. 2001;89:930-4.
18. Grainger DJ, Kemp PR, Metcalfe JC, et al. The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis. Nat Med. 1995;1:74-9.
19. WangXL, Liu SX,WilckenDE. Circulating transforming growth factor beta 1 and coronary artery disease. Cardiovasc Res. 1997;34:404-10.
20. Jiang X, Zeng HS, Guo Y, et al. The expression of matrix metalloproteinases-9, transforming growth factor-betal and transforming growth factor-beta receptor Ⅰ in human atherosclerotic plaque and their relationship with plaque stability. Chin Med J (Engl). 2004; 117:1825-9.
21. Bobik A, Agrotis A, Kanellakis P, et al. Distinct patterns of transforming growth factor-beta isoform and receptor expression in human atherosclerotic lesions. Colocalization implicates TGF-beta in fibrofatty lesion development. Circulation. 1999;99:2883-91.
22. Piao M, Tokunaga O. Significant expression of endoglin (CD105), TGFbeta-1 and TGFbeta R-2 in the atherosclerotic aorta: an immunohistological study. J Atheroscler Thromb. 2006; 13:82-9.
23. Grainger DJ, Heathcote K, Chiano M, et al. Genetic control of the circulating concentration of transforming growth factor type betal. Hum Mol Genet. 1999;8:93-7.
24. Silverman ES, Palmer LJ, Subramaniam V, et al. Transforming growth factor-beta 1 promoter polymorphism C-509T is associated with asthma. Am J Respir Crit Care Med.2004;169:214-9.
25. Luedecking EK, DeKosky ST, Mehdi H, et al. Analysis of genetic polymorphisms in the transforming growth factorbetal gene and the risk of Alzheimer's disease. Hum Genet. 2000;106:565-9.
26. Awad MR, El-Gamel A, Hasleton P, et al. Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation. 1998;66:1014-20.
27. Suthanthiran M, Li B, Song JO,DingR, et al. Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: a novelmediator of hypertension and/or target organ damage. Proc Natl Acad Sci U S A. 2000;97:3479-84.
28. Yamada Y, Miyauchi A, Goto J, et al. Association of a polymorphism of the transforming growth factorbetal gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J Bone Miner Res. 1998; 13:1569-76.
29. Yokota M, Ichihara S, Lin TL, et al. Association of a T29-NC polymorphism of the transforming growth factor-betal gene with genetic susceptibility to myocardial infarction in Japanese. Circulation. 2000; 101:2783-7.
30. Cambien F, Ricard S, Troesch A,Mallet C, et al. Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de l'Infarctus du Myocarde (ECTIM) Study. Hypertension.1996;28:881-7.
31. Tang B, Bottinger EP, Jakowlew SB, et al. Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency. Nat Med. 1998;4:802-7.
32. Lutgens E, Gijbels M, Smook M, et al. Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. Arterioscler Thromb Vasc Biol. 2002;22:975-82.
33. Gojova A, Brun V, Esposito B, et al. Specific abrogation of transforming growth factor-{beta} signaling in T cells alters atherosclerotic lesion size and composition in mice. Blood. 2003.
34. Robertson AK, Rudling M, Zhou X, et al. Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest. 2003;112:1342-50.
35. ten Dijke P, Hill CS. New insights into TGF-beta-Smad signalling. Trends Biochem Sci. 2004;29:265-73.
36. McCaffrey TA, Consigli S, Du B, et al. Decreased type Ⅱ/type I TGF-βreceptor ratio in cells derived from human atherosclerotic lesions. Conversion from an antiproliferative to profibrotic response to TGF-β . J Clin Invest. 1995;96:2667-2675.
37. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685-700.
38. Moustakas A, Heldin CH. Non-Smad TGF-beta signals. J Cell Sci. 2005;118:3573-84.
39. McCaffrey TA, Du B, Consigli S, et al. Genomic instability in the type Ⅱ TGF-beta1 receptor gene in atherosclerotic and restenotic vascular cells. J Clin Invest. 1997; 100:2182-8.
40. Evanko SP, Raines EW, Ross R, et al. Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics, and the proximity of platelet-derived growth factor and transforming growth factor-beta. Am J Pathol.1998;152: 533-46.
41. Li CG, Bethell H, Wilson PB, et al. The significance of CD105, TGFbeta and CD105/TGFbeta complexes in coronary artery disease. Atherosclerosis. 2000; 152:249-56.
42. Kalinina N, Agrotis A, Antropova Y, et al. Smad expression in human atherosclerotic lesions: evidence for impaired TGF-beta/Smad signaling in smooth muscle cells of fibrofatty lesions. Arterioscler Thromb Vasc Biol. 2004;24:1391-6.
43. Oshima M, Oshima H, Taketo MM. TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol. 1996; 179:297-302.
44. Disabella E, Grasso M, Marziliano N, et al. Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects. Eur J Hum Genet. 2006; 14:34-8.
45. Singh KK, Rommel K, Mishra A, et al. TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat.2006;27:770-7.
46. Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352:337-9.
47. Lee B, Godfrey M, Vitale E, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature. 1991;352:330-4.
48. Maslen CL, Corson GM, Maddox BK, et al. Partial sequence of a candidate gene for the Marfan syndrome. Nature. 1991;352:334-7.
49. Saharinen J, Hyytiainen M, Taipale J, et al. Latent transforming growth factor-beta binding proteins (LTBPs)-structural extracellular matrix proteins for targeting TGF-beta action. Cytokine Growth Factor Rev. 1999; 10:99-117.
50. Veillard NR, Steffens S, Burger F, et al. Differential expression patterns of proinflammatory and antiinflammatory mediators during atherogenesis in mice. Arterioscler Thromb Vasc Biol. 2004;24: 2339-2344.
51. Ait-Oufella H, Salomon BL, Potteaux S, et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med. 2006; 12:178 -180.
52. Fahlen L, Read S, Gorlik L, et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J Exp Med. 2005;201:737-746.
53. Marie JC, Letterio JJ, Gavin M, et al. TGF- β 1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med. 2005;201:1061-1067.
54. Li D, Liu Y, Chen J, et al. Suppression of atherogenesis by delivery of TGFbeta 1ACT using adeno-associated virus type 2 in LDLR knockout mice. Biochem Biophys Res Commun. 2006;344:701-7.
55. Koglin J, Glysing-Jensen T, Raisanen-Sokolowski A, et al. Immune sources of transforming growth factor-beta1 reduce transplant arteriosclerosis: insight derived from a knockout mouse model. Circ Res. 1998;83:652-60.
56. Nabel EG, Shum L, Pompili VJ, et al. Direct transfer of transforming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia. Proc Natl Acad Sci U S A.1993;90:10759-63.
57. Grainger DJ, Weissberg PL, Metcalfe JC. Tamoxifen decreases the rate of proliferation of rat vascular smooth-muscle cells in culture by inducing production of transforming growth factor beta. Biochem J. 1993;294(Pt 1):109-12.
58. Grainger DJ, Kirschenlohr HL, Metcalfe JC, et al. Proliferation of human smooth muscle cells promoted by lipoprotein(a). Science. 1993;260:1655-8.
59. Clarke SC, Schofield PM, Grace AA, et al. Tamoxifen effects on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis. Circulation.2001; 103:1497-502.
60. Grainger DJ. Transforming growth factor beta and atherosclerosis: so far, so good for the protective cytokine hypothesis. Arterioscler Thromb Vasc Biol. 2004;24:399-404.
61. Grainger DJ, Schofield PM. Tamoxifen for the prevention of myocardial infarction in humans: preclinical and early clinical evidence. Circulation. 2005; 112:3018-24.
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