血浆HSP70抗体水平在动脉粥样硬化形成过程中的变化及其生物学作用的研究
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摘要
动脉粥样硬化(atherosclerosis,AS)是严重影响人类健康的心血管疾病之一。动脉粥样硬化的发病机制复杂,近年来研究认为,免疫机制是动脉粥样硬化发生发展的主要病理机制之一,但已有的研究尚难以完全解释其发生的分子机制。在对动脉粥样硬化病因机制的探寻中越来越多的研究报告显示了热休克蛋白70(heat shock protein 70, HSP70)和HSP70抗体与动脉粥样硬化的相关性。研究发现,在冠心病、动脉粥样硬化和高血压患者的血浆中不仅HSP70水平显著升高,而且发现其抗体的存在;流行病学调查进一步显示,血浆中显著升高的HSP70抗体的浓度与疾病的严重程度具有相关性,这种相关性不受年龄、性别和其他危险因素的影响。这些研究结果表明血浆HSP70升高和HSP70抗体的出现参与了心血管疾病发生发展的病理机制,但动脉粥样硬化形成过程血浆HSP70抗体水平变化及参与动脉粥样硬化发生发展的病理机制并不清楚。为阐明动脉粥样硬化形成过程中血浆HSP70抗体的作用机制,本研究建立大鼠动脉粥样硬化动物模型,认识动脉粥样硬化形成过程中血浆HSP70抗体水平动态变化,探索血浆HSP70抗体在动脉粥样硬化形成过程中产生的机制;并进一步研究血浆HSP70抗体在动脉粥样硬化形成过程中的作用及其生物学机制,为揭示动脉粥样硬化发病机制,探寻动脉粥样硬化防治措施提供新的科学依据。
一、动脉粥样硬化形成过程中血浆HSP70抗体水平的变化
本研究采用高脂膳食喂养Wistar大鼠10w,以大鼠血脂水平和主动脉病理学观察确认动脉粥样硬化动物模型建立,结果显示,高脂组大鼠高脂膳食2w,大鼠血浆总胆固醇(TC)、低密度脂蛋白(LDL)水平较对照组显著升高,且随着动脉粥样硬化的发生发展逐渐升高;而血浆甘油三酯和高密度脂蛋白水平与对照组相比无明显差异。大鼠主动脉病理学检查显示,大鼠高脂膳食10w后血管壁内膜增厚,形成片状或点状钙化的动脉粥样硬化斑块典型病理改变,表明成功建立动脉粥样硬化动物模型。采用ELISA方法检测大鼠动脉粥样硬化形成过程中血浆HSP70抗体水平,结果显示:高脂组大鼠高脂膳食4w,大鼠血浆总HSP70 IgG和IgM抗体水平均显著高于对照组,早于大鼠主动脉出现病理改变时间(6w),并随动脉粥样硬化形成过程逐渐升高; 10w时,高脂组大鼠血浆总IgG、IgG1、IgM水平显著高于对照组和0w,而IgA、IgG2a,IgG2b水平无显著改变。表明动脉粥样硬化形成过程中血浆HSP70抗体水平显著升高,动脉粥样硬化大鼠血浆HSP70抗体亚类水平发生改变。
为探索血浆HSP70抗体产生的机制,进一步检测大鼠动脉粥样硬化形成过程中血浆HSP70水平,结果显示,高脂组大鼠高脂膳食2w,大鼠血浆HSP70水平显著高于对照组(0.18±0.021 g/ml vs 0.087±0.014 g/ml),随着动脉粥样硬化发生发展逐渐升高;蛋白免疫印记检测大鼠血浆HSP70复合物水平变化,发现动脉粥样硬化大鼠血浆HSP70复合物种类及含量显著高于对照组,提示血浆HSP70水平升高及血浆HSP70复合物水平变化是血浆HSP70抗体产生的机制之一。
二、动脉粥样硬化形成过程中HSP70抗体的作用及其生物学机制
为观察血浆HSP70抗体在动脉粥样硬化形成过程中的作用,采用杂交瘤技术研制HSP70单克隆抗体BD091,竞争ELISA方法显示,BD091与血浆HSP70抗体具有相同结合位点。采用抗体尾静脉注射方法给予大鼠HSP70抗体BD091(IgG1,aa 384-642)或SPA-810 (aa 437-504),结果显示:BD091抗体可以诱导大鼠血管损伤,增加动脉粥样硬化脂质斑块面积及斑块内SMCs、MΦ、T细胞数目,提高斑块中细胞间粘附分子-1(ICAM-1)/单核细胞趋化因子(MCP-1)表达水平; SPA-810对动脉粥样硬化形成无显著影响。同时检测大鼠血脂水平,与对照组比较,HSP70抗体处理组大鼠血脂水平未发生显著改变;表明识别HSP70特异性位点的HSP70抗体可以促进动脉粥样硬化形成,这种作用不会改变大鼠血脂水平。
OxLDL是动脉粥样硬化发生的危险因素,可以诱导血管内皮细胞HSP70表达水平升高。大鼠动脉粥样硬化形成过程中,大鼠血浆OxLDL水平显著高于对照组,与血浆HSP70抗体水平显著相关。采用20 g/ml OxLDL干预血管内皮细胞12h,使血管内皮细胞HSP70表达水平升高,诱导HSP70定位于细胞膜的HSP70增多。为研究HSP70抗体对血管内皮细胞的损伤作用,给予血管内皮细胞20 g/ml OxLDL 12h,未见细胞培养中LDH水平显著升高;而当再加入HSP70抗体和补体或外周血淋巴细胞后,细胞培养液中LDH水平显著升高;表明HSP70抗体能够诱导血管内皮细胞损伤。
为进一步研究血浆HSP70抗体的作用机制,采用改良ELISA方法检测大鼠动脉粥样硬化形成过程中血浆HSP70抗原抗体复合物(HSP70-IC)水平,结果显示,高脂组大鼠高脂膳食8w后血浆HSP70-IC水平较对照组显著升高,且随着疾病的发生发展逐步升高,提示HSP70-IC参与动脉粥样硬化形成过程。应用PEG沉淀法制备HSP70-IC(BD091-IC),采用细胞ELISA方法检测外周血淋巴细胞粘附血管内皮细胞数目,结果显示:HSP70-IC可以粘附于血管内皮细胞,诱导细胞ICAM-1表达水平升高,并增加外周血淋巴细胞粘附血管内皮细胞数目;而单独给予血管内皮细胞BD091或HSP70对外周血淋巴细胞粘附血管内皮细胞无显著影响;表明HSP70-IC可以介导外周血淋巴细胞粘附于血管内皮细胞。
为观察HSP70-IC对平滑肌细胞的影响,应用组织块培养法培养大鼠血管平滑肌细胞,采用MTT和流式细胞术方法检测平滑肌细胞增殖水平,结果发现50 g/ml以上浓度HSP70-IC可以诱导平滑肌细胞增殖,增加平滑肌细胞培养液中PDGF-BB、MCP-1水平。应用划痕实验和Boyden Chamber实验观察到HSP70-IC可以诱导平滑肌细胞的迁移。Fcγ受体(FcγRs)是位于细胞膜表面的IC特异性受体。采用荧光实时定量PCR方法检测平滑肌细胞FcγRs表达水平,结果显示,50 g/ml HSP70-IC干预平滑肌细胞6h后,细胞FcγRI、FcγRIII表达水平较对照组显著升高,并随着HSP70-IC干预浓度的提高而升高;而单独给予平滑肌细胞BD091和HSP70未见导致平滑肌细胞FcγRI和FcγRIII表达水平显著变化,表明HSP70-IC可以诱导平滑肌细胞FcγRI和FcγRIII表达;应用蛋白免疫印记方法检测平滑肌细胞NF-κB/ERK通路活化状态,发现50 g/ml HSP70-IC可以诱导平滑肌细NF-κB/ERK通路活化。上述结果提示,HSP70-IC可诱导平滑肌细胞FcγRs表达升高,HSP70-IC与FcγRs相互作用,激活NF-κB/ERK通路,促使平滑肌细胞分泌细胞因子,导致平滑肌细胞增殖与迁移。
综上所述,高脂膳食所致大鼠动脉粥样硬化形成过程中,血浆HSP70水平升高和血浆HSP70复合物异常增多导致血浆HSP70抗体产生,并继而诱导大鼠主动脉内皮损伤,增加动脉粥样硬化斑块面积及斑块内浸润细胞数目,提高斑块中炎症因子水平,促进动脉粥样硬化形成;HSP70抗体促进大鼠动脉粥样硬化可能通过诱导血管内皮细胞损伤,与血浆HSP70形成HSP70-IC,并诱导外周血淋巴细胞粘附于血管内皮细胞,促进血管平滑肌细胞增殖与迁移而实现的。
Atherosclerosis (atherosclerosis, AS) is a serious impact on human health of cardiovascular disease. The pathogenesis of atherosclerosis is very complicated. Recently, the study suggests that inflammatory and immune mechanisms are the major pathological mechanism during the development of atherosclerosis. However, the existing studies have been difficult to fully explain the molecular mechanism of AS. During explore the etiology mechanism of atherosclerosis, more and more studies indicate that there was a correlation between the heat shock protein 70 (heat shock protein 70, HSP70) and HSP70 antibodies with atherosclerosis. Studies found that there were not only significantly increased levels of plasma HSP70, but the presence of antibodies in coronary heart disease, atherosclerosis and hypertension patients. Further epidemiological investigation showed there was a correlation between significantly elevated plasma HSP70 antibodies and the severity of disease, this relationship regardless of age, gender and other risk factors. These results show that the increased plasma HSP70 and appeared HSP70 antibodies were involved in the pathological mechanism of the progression of cardiovascular disease. However, it is not clear that plasma levels of HSP70 antibody changes the formation of atherosclerosis. And it is also not clear that the pathological mechanism of plasma HSP70 antibody involved in the development of atherosclerosis. To elucidating the role of plasma HSP70 autoantibody in the procession of atherosclerosis, in this study, we developed animal models of atherosclerosis. We systematically observed the dynamic level changes of plasma HSP70 antibody, and to explore the resource of plasma HSP70 antibody in the procession of atherosclerosis. And we further study the role of plasma HSP70 antibody in the formation of atherosclerosis and its pathological mechanism of atherosclerosis. These results will reveal the pathogenesis of atherosclerosis, and provide us new scientific evidence of atherosclerosis prevention and treatment.
1. Change of plasma HSP70 antibody levels during the formation of Atherosclerosis
In this study, atherosclerotic animal model was developed by fed on high fat diet for 10 weeks. Atherosclerotic animal model was assessed by serum lipid levels and pathological confirmation of aortic atherosclerosis. At 2w of high fat diet, rat plasma total cholesterol (TC), low density lipoprotein (LDL) levels were significantly higher than the control group, and with the development of disease showing the trend of gradual increase. While the high-density lipoprotein and triglycerides in plasma were not significantly different with control. Pathological examination showed that rats vessel wall intima thickening, formation of flakes or punctuates calcification at 10w in HCD, Which were the arteries pathological changes in atherosclerotic plaque. These results suggest that AS animal model was developed successfully. The plasma HSP70 antibody levels determined by ELISA showed: rat plasma total HSP70 IgG and IgM antibodies were significantly higher in HCD than control at 4w, which were earlier than pathological changes occur in rat aortic time point (6w). And with the occurrence of atherosclerosis development occurs gradually increased. At 10w, the total IgG, IgG1, IgM subtype were significantly higher in AS group than control. While the IgA, IgG2a, IgG2b subclass levels were not significantly changed. HSP70 antibody subclass levels between 0w and 10w in AS group were showed the same trend. These result showed that the level of plasma HSP70 antibodies were significantly increased during the formation of atherosclerosis. And the plasma HSP70 antibody subclass levels were changed during the progression of atherosclerosis.
To explore the mechanism of plasma HSP70 antibody production, the levels of plasma HSP70 were further tested. Plasma HSP70 ELISA results showed that HSP70 plasma levels in AS group were significantly increased at 2w (0.18±0.021 g/ml vs 0.087±0.014 g/ml), which was gradually increased with time trend. Plasma HSP70 complex was detected by western Blotting. The results showed that plasma HSP70 complex species in AS group were significantly higher than control. Prompted increased plasma levels of HSP70 and plasma HSP70 complex may be the source of plasma HSP70 antibodies.
2. The role of HSP70 antibody and its pathological mechanism during the formation of atherosclerosis
To observe the role of plasma HSP70 antibody during the formation of atherosclerosis, BD091 monoclonal antibody was developed by hybridoma technology. BD091 had the same binding site with plasma HSP70 antibody by competition ELISA. Rats were treated with HSP70 antibody BD091(IgG1,aa 384-642) or SPA-810 (aa 437-504) by intravenous injection. BD091 could induce vascular injury, and increase the areas of atherosclerotic plaque and the numbers of SMCs、MΦ、T in plaque. BD091 also could improve the expression of ICAM-1/MCP-1 in plaque. The SPA-810 antibody had no effect on the formation of atherosclerosis. The serum lipid levels were not changed between antibody treated group and untreated group. These results suggest that specific site of HSP70 antibody can promote the formation of atherosclerosis; this role will not change the blood lipid levels in rats.
OxLDL is atherosclerosis risk factors, which could induce elevated level of HSP70 expression of vascular endothelial cells. Plasma OxLDL levels were significantly higher than control, and were significantly correlated with levels of plasma HSP70 antibody. High level of HSP70 was expressed in vascular endothelial cells which were treated with 20 g/ml OxLDL for 12h, and induced increased HSP70 localized in the cell membrane. In order to study the damaged effect of HSP70 antibodies on vascular endothelial cell, vascular endothelial cell culture LDH were not significantly increased after treated with 20 g/ml OxLDL for 12h. Cell culture LDH were significantly increased after added HSP70 antibody and complement or peripheral blood lymphocytes. This suggested that HSP70 antibody could induce vascular endothelial cell injury. The level of plasma HSP70-IC in AS rat was significantly higher than control at 8w, increased gradually with time. This suggested that HSP70-IC were involved in the formation of atherosclerosis. Application of PEG precipitation method HSP70-IC (BD091-IC), the numbers of peripheral blood lymphocytes adhere to endothelial cells determined by ELISA. HSP70-IC can adhere to endothelial cells and induced elevated levels of ICAM-1 in endothelial cells, and increase the cell number of peripheral blood lymphocyte adhere to endothelial cells. There were no significant effect of peripheral blood lymphocytes adhered to endothelial cells treated with HSP70 or BD091alone.This suggest that HSP70-IC may mediate lymphocyte adhesion to vascular endothelial cells.
To observe the HSP70-IC on the smooth muscle cells, rat vascular smooth muscle cells were cultured using tissue culture. Smooth muscle cells proliferations were determined by MTT and flow cytometry. 50 g/ml concentration of HSP70-IC above can induce smooth muscle cell proliferation, increased the levels of smooth muscle cell culture medium PDGF-BB, MCP-1. HSP70-IC could induce smooth muscle cell migration by using wound healing assay and Boyden Chamber experiment. Fcγreceptors (FcγRs) are located on cell surface which specifically interacted with IC. By using fluorescence real-time quantitative PCR, the level of SMCs FcγRI, FcγRIII expression were increased after incubated with 50 g/ml BD091-IC for 6h. The levels of FcγRs expression were depended on BD091-IC concentration. After incubated with BD091 or HSP70 alone, the level of SMCs FcγRI, FcγRIII expression was not increased. These results suggested that HSP70-IC could induce FcγRI and FcγRIII expression on smooth muscle cells. 50 g/ml HSP70-IC could induce smooth muscle NF-κB/ERK pathway activated by western blotting. These results suggested that, HSP70-IC could induce increased FcγRs expression of smooth muscle cell, HSP70-IC interaction with FcγRs, activated NF-κB/ERK pathway to promote smooth muscle cells to produce cytokines, leading to smooth muscle cell proliferation and migration.
In summary, during the formation of AS induced by high-fat diet, it may be the cause of HSP70 antibody production owing to high plasma HSP70 level or changed plasma HSP70 complex, And then induced aortic endothelial damage, increased atherosclerotic plaque size and the number of infiltrating cells in plaque, raising the level of the inflammatory factors in plaque, playing a harmful role in promoting the formation of atherosclerosis. The atherosclerotic rat plasma HSP70 antibodies were involved in the pathogenesis of AS by accelerating the process. HSP70 antibody play a damaged role through endothelial cells injury induced by HSP70 antibody, or formatting HSP70-IC, mediated PBL adhesion to endothelial cells, promoted smooth muscle cell proliferation and migration.
一、动脉粥样硬化形成过程中血浆HSP70抗体水平的变化
本研究采用高脂膳食喂养Wistar大鼠10w,以大鼠血脂水平和主动脉病理学观察确认动脉粥样硬化动物模型建立,结果显示,高脂组大鼠高脂膳食2w,大鼠血浆总胆固醇(TC)、低密度脂蛋白(LDL)水平较对照组显著升高,且随着动脉粥样硬化的发生发展逐渐升高;而血浆甘油三酯和高密度脂蛋白水平与对照组相比无明显差异。大鼠主动脉病理学检查显示,大鼠高脂膳食10w后血管壁内膜增厚,形成片状或点状钙化的动脉粥样硬化斑块典型病理改变,表明成功建立动脉粥样硬化动物模型。采用ELISA方法检测大鼠动脉粥样硬化形成过程中血浆HSP70抗体水平,结果显示:高脂组大鼠高脂膳食4w,大鼠血浆总HSP70 IgG和IgM抗体水平均显著高于对照组,早于大鼠主动脉出现病理改变时间(6w),并随动脉粥样硬化形成过程逐渐升高; 10w时,高脂组大鼠血浆总IgG、IgG1、IgM水平显著高于对照组和0w,而IgA、IgG2a,IgG2b水平无显著改变。表明动脉粥样硬化形成过程中血浆HSP70抗体水平显著升高,动脉粥样硬化大鼠血浆HSP70抗体亚类水平发生改变。
为探索血浆HSP70抗体产生的机制,进一步检测大鼠动脉粥样硬化形成过程中血浆HSP70水平,结果显示,高脂组大鼠高脂膳食2w,大鼠血浆HSP70水平显著高于对照组(0.18±0.021 g/ml vs 0.087±0.014 g/ml),随着动脉粥样硬化发生发展逐渐升高;蛋白免疫印记检测大鼠血浆HSP70复合物水平变化,发现动脉粥样硬化大鼠血浆HSP70复合物种类及含量显著高于对照组,提示血浆HSP70水平升高及血浆HSP70复合物水平变化是血浆HSP70抗体产生的机制之一。
二、动脉粥样硬化形成过程中HSP70抗体的作用及其生物学机制
为观察血浆HSP70抗体在动脉粥样硬化形成过程中的作用,采用杂交瘤技术研制HSP70单克隆抗体BD091,竞争ELISA方法显示,BD091与血浆HSP70抗体具有相同结合位点。采用抗体尾静脉注射方法给予大鼠HSP70抗体BD091(IgG1,aa 384-642)或SPA-810 (aa 437-504),结果显示:BD091抗体可以诱导大鼠血管损伤,增加动脉粥样硬化脂质斑块面积及斑块内SMCs、MΦ、T细胞数目,提高斑块中细胞间粘附分子-1(ICAM-1)/单核细胞趋化因子(MCP-1)表达水平; SPA-810对动脉粥样硬化形成无显著影响。同时检测大鼠血脂水平,与对照组比较,HSP70抗体处理组大鼠血脂水平未发生显著改变;表明识别HSP70特异性位点的HSP70抗体可以促进动脉粥样硬化形成,这种作用不会改变大鼠血脂水平。
OxLDL是动脉粥样硬化发生的危险因素,可以诱导血管内皮细胞HSP70表达水平升高。大鼠动脉粥样硬化形成过程中,大鼠血浆OxLDL水平显著高于对照组,与血浆HSP70抗体水平显著相关。采用20 g/ml OxLDL干预血管内皮细胞12h,使血管内皮细胞HSP70表达水平升高,诱导HSP70定位于细胞膜的HSP70增多。为研究HSP70抗体对血管内皮细胞的损伤作用,给予血管内皮细胞20 g/ml OxLDL 12h,未见细胞培养中LDH水平显著升高;而当再加入HSP70抗体和补体或外周血淋巴细胞后,细胞培养液中LDH水平显著升高;表明HSP70抗体能够诱导血管内皮细胞损伤。
为进一步研究血浆HSP70抗体的作用机制,采用改良ELISA方法检测大鼠动脉粥样硬化形成过程中血浆HSP70抗原抗体复合物(HSP70-IC)水平,结果显示,高脂组大鼠高脂膳食8w后血浆HSP70-IC水平较对照组显著升高,且随着疾病的发生发展逐步升高,提示HSP70-IC参与动脉粥样硬化形成过程。应用PEG沉淀法制备HSP70-IC(BD091-IC),采用细胞ELISA方法检测外周血淋巴细胞粘附血管内皮细胞数目,结果显示:HSP70-IC可以粘附于血管内皮细胞,诱导细胞ICAM-1表达水平升高,并增加外周血淋巴细胞粘附血管内皮细胞数目;而单独给予血管内皮细胞BD091或HSP70对外周血淋巴细胞粘附血管内皮细胞无显著影响;表明HSP70-IC可以介导外周血淋巴细胞粘附于血管内皮细胞。
为观察HSP70-IC对平滑肌细胞的影响,应用组织块培养法培养大鼠血管平滑肌细胞,采用MTT和流式细胞术方法检测平滑肌细胞增殖水平,结果发现50 g/ml以上浓度HSP70-IC可以诱导平滑肌细胞增殖,增加平滑肌细胞培养液中PDGF-BB、MCP-1水平。应用划痕实验和Boyden Chamber实验观察到HSP70-IC可以诱导平滑肌细胞的迁移。Fcγ受体(FcγRs)是位于细胞膜表面的IC特异性受体。采用荧光实时定量PCR方法检测平滑肌细胞FcγRs表达水平,结果显示,50 g/ml HSP70-IC干预平滑肌细胞6h后,细胞FcγRI、FcγRIII表达水平较对照组显著升高,并随着HSP70-IC干预浓度的提高而升高;而单独给予平滑肌细胞BD091和HSP70未见导致平滑肌细胞FcγRI和FcγRIII表达水平显著变化,表明HSP70-IC可以诱导平滑肌细胞FcγRI和FcγRIII表达;应用蛋白免疫印记方法检测平滑肌细胞NF-κB/ERK通路活化状态,发现50 g/ml HSP70-IC可以诱导平滑肌细NF-κB/ERK通路活化。上述结果提示,HSP70-IC可诱导平滑肌细胞FcγRs表达升高,HSP70-IC与FcγRs相互作用,激活NF-κB/ERK通路,促使平滑肌细胞分泌细胞因子,导致平滑肌细胞增殖与迁移。
综上所述,高脂膳食所致大鼠动脉粥样硬化形成过程中,血浆HSP70水平升高和血浆HSP70复合物异常增多导致血浆HSP70抗体产生,并继而诱导大鼠主动脉内皮损伤,增加动脉粥样硬化斑块面积及斑块内浸润细胞数目,提高斑块中炎症因子水平,促进动脉粥样硬化形成;HSP70抗体促进大鼠动脉粥样硬化可能通过诱导血管内皮细胞损伤,与血浆HSP70形成HSP70-IC,并诱导外周血淋巴细胞粘附于血管内皮细胞,促进血管平滑肌细胞增殖与迁移而实现的。
Atherosclerosis (atherosclerosis, AS) is a serious impact on human health of cardiovascular disease. The pathogenesis of atherosclerosis is very complicated. Recently, the study suggests that inflammatory and immune mechanisms are the major pathological mechanism during the development of atherosclerosis. However, the existing studies have been difficult to fully explain the molecular mechanism of AS. During explore the etiology mechanism of atherosclerosis, more and more studies indicate that there was a correlation between the heat shock protein 70 (heat shock protein 70, HSP70) and HSP70 antibodies with atherosclerosis. Studies found that there were not only significantly increased levels of plasma HSP70, but the presence of antibodies in coronary heart disease, atherosclerosis and hypertension patients. Further epidemiological investigation showed there was a correlation between significantly elevated plasma HSP70 antibodies and the severity of disease, this relationship regardless of age, gender and other risk factors. These results show that the increased plasma HSP70 and appeared HSP70 antibodies were involved in the pathological mechanism of the progression of cardiovascular disease. However, it is not clear that plasma levels of HSP70 antibody changes the formation of atherosclerosis. And it is also not clear that the pathological mechanism of plasma HSP70 antibody involved in the development of atherosclerosis. To elucidating the role of plasma HSP70 autoantibody in the procession of atherosclerosis, in this study, we developed animal models of atherosclerosis. We systematically observed the dynamic level changes of plasma HSP70 antibody, and to explore the resource of plasma HSP70 antibody in the procession of atherosclerosis. And we further study the role of plasma HSP70 antibody in the formation of atherosclerosis and its pathological mechanism of atherosclerosis. These results will reveal the pathogenesis of atherosclerosis, and provide us new scientific evidence of atherosclerosis prevention and treatment.
1. Change of plasma HSP70 antibody levels during the formation of Atherosclerosis
In this study, atherosclerotic animal model was developed by fed on high fat diet for 10 weeks. Atherosclerotic animal model was assessed by serum lipid levels and pathological confirmation of aortic atherosclerosis. At 2w of high fat diet, rat plasma total cholesterol (TC), low density lipoprotein (LDL) levels were significantly higher than the control group, and with the development of disease showing the trend of gradual increase. While the high-density lipoprotein and triglycerides in plasma were not significantly different with control. Pathological examination showed that rats vessel wall intima thickening, formation of flakes or punctuates calcification at 10w in HCD, Which were the arteries pathological changes in atherosclerotic plaque. These results suggest that AS animal model was developed successfully. The plasma HSP70 antibody levels determined by ELISA showed: rat plasma total HSP70 IgG and IgM antibodies were significantly higher in HCD than control at 4w, which were earlier than pathological changes occur in rat aortic time point (6w). And with the occurrence of atherosclerosis development occurs gradually increased. At 10w, the total IgG, IgG1, IgM subtype were significantly higher in AS group than control. While the IgA, IgG2a, IgG2b subclass levels were not significantly changed. HSP70 antibody subclass levels between 0w and 10w in AS group were showed the same trend. These result showed that the level of plasma HSP70 antibodies were significantly increased during the formation of atherosclerosis. And the plasma HSP70 antibody subclass levels were changed during the progression of atherosclerosis.
To explore the mechanism of plasma HSP70 antibody production, the levels of plasma HSP70 were further tested. Plasma HSP70 ELISA results showed that HSP70 plasma levels in AS group were significantly increased at 2w (0.18±0.021 g/ml vs 0.087±0.014 g/ml), which was gradually increased with time trend. Plasma HSP70 complex was detected by western Blotting. The results showed that plasma HSP70 complex species in AS group were significantly higher than control. Prompted increased plasma levels of HSP70 and plasma HSP70 complex may be the source of plasma HSP70 antibodies.
2. The role of HSP70 antibody and its pathological mechanism during the formation of atherosclerosis
To observe the role of plasma HSP70 antibody during the formation of atherosclerosis, BD091 monoclonal antibody was developed by hybridoma technology. BD091 had the same binding site with plasma HSP70 antibody by competition ELISA. Rats were treated with HSP70 antibody BD091(IgG1,aa 384-642) or SPA-810 (aa 437-504) by intravenous injection. BD091 could induce vascular injury, and increase the areas of atherosclerotic plaque and the numbers of SMCs、MΦ、T in plaque. BD091 also could improve the expression of ICAM-1/MCP-1 in plaque. The SPA-810 antibody had no effect on the formation of atherosclerosis. The serum lipid levels were not changed between antibody treated group and untreated group. These results suggest that specific site of HSP70 antibody can promote the formation of atherosclerosis; this role will not change the blood lipid levels in rats.
OxLDL is atherosclerosis risk factors, which could induce elevated level of HSP70 expression of vascular endothelial cells. Plasma OxLDL levels were significantly higher than control, and were significantly correlated with levels of plasma HSP70 antibody. High level of HSP70 was expressed in vascular endothelial cells which were treated with 20 g/ml OxLDL for 12h, and induced increased HSP70 localized in the cell membrane. In order to study the damaged effect of HSP70 antibodies on vascular endothelial cell, vascular endothelial cell culture LDH were not significantly increased after treated with 20 g/ml OxLDL for 12h. Cell culture LDH were significantly increased after added HSP70 antibody and complement or peripheral blood lymphocytes. This suggested that HSP70 antibody could induce vascular endothelial cell injury. The level of plasma HSP70-IC in AS rat was significantly higher than control at 8w, increased gradually with time. This suggested that HSP70-IC were involved in the formation of atherosclerosis. Application of PEG precipitation method HSP70-IC (BD091-IC), the numbers of peripheral blood lymphocytes adhere to endothelial cells determined by ELISA. HSP70-IC can adhere to endothelial cells and induced elevated levels of ICAM-1 in endothelial cells, and increase the cell number of peripheral blood lymphocyte adhere to endothelial cells. There were no significant effect of peripheral blood lymphocytes adhered to endothelial cells treated with HSP70 or BD091alone.This suggest that HSP70-IC may mediate lymphocyte adhesion to vascular endothelial cells.
To observe the HSP70-IC on the smooth muscle cells, rat vascular smooth muscle cells were cultured using tissue culture. Smooth muscle cells proliferations were determined by MTT and flow cytometry. 50 g/ml concentration of HSP70-IC above can induce smooth muscle cell proliferation, increased the levels of smooth muscle cell culture medium PDGF-BB, MCP-1. HSP70-IC could induce smooth muscle cell migration by using wound healing assay and Boyden Chamber experiment. Fcγreceptors (FcγRs) are located on cell surface which specifically interacted with IC. By using fluorescence real-time quantitative PCR, the level of SMCs FcγRI, FcγRIII expression were increased after incubated with 50 g/ml BD091-IC for 6h. The levels of FcγRs expression were depended on BD091-IC concentration. After incubated with BD091 or HSP70 alone, the level of SMCs FcγRI, FcγRIII expression was not increased. These results suggested that HSP70-IC could induce FcγRI and FcγRIII expression on smooth muscle cells. 50 g/ml HSP70-IC could induce smooth muscle NF-κB/ERK pathway activated by western blotting. These results suggested that, HSP70-IC could induce increased FcγRs expression of smooth muscle cell, HSP70-IC interaction with FcγRs, activated NF-κB/ERK pathway to promote smooth muscle cells to produce cytokines, leading to smooth muscle cell proliferation and migration.
In summary, during the formation of AS induced by high-fat diet, it may be the cause of HSP70 antibody production owing to high plasma HSP70 level or changed plasma HSP70 complex, And then induced aortic endothelial damage, increased atherosclerotic plaque size and the number of infiltrating cells in plaque, raising the level of the inflammatory factors in plaque, playing a harmful role in promoting the formation of atherosclerosis. The atherosclerotic rat plasma HSP70 antibodies were involved in the pathogenesis of AS by accelerating the process. HSP70 antibody play a damaged role through endothelial cells injury induced by HSP70 antibody, or formatting HSP70-IC, mediated PBL adhesion to endothelial cells, promoted smooth muscle cell proliferation and migration.
引文
1. Stary HC, C.A., Dinsmore RE, et al, A definition of advanced types of atherosclerotic lesions and histological classification of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Atherosclerosis, American Heart Association special report. Circulation, 1995. 92: p. 1355-1374.
2. P, L., Inflammation in atherosclerosis. Nature 2002. 420: p. 868-874.
3. Hansson GK, B.G., Bylock A, Hjalmarsson L., Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol, 2001. 21: p. 1876-1890.
4. Wick G, X.Q., Atherosclerosis--an autoimmune disease! Exp Gerontol, 1999. 34(4): p. 559-566.
5. Ritossa, F., A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia, 1962: p. 571-573.
6. Tissieres, A., Mitchell HK, Tracy UM, Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs. J Mol Bio, 1974. 84(3): p. 389-398.
7. Lindquist S, C.E., The heat shock proteins. Annu Rev Genet, , 1988. 22: p. 631-677.
8. Multhoff G, B.C., Wiesnet M, Müller E, Meier T, Wilmanns W, Issels RD., A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. Int J Cancer 1995. 61(2): p. 272-9.
9. MULTHOFF, G., BOTZLER, C., JENNEN, L., SCHMIDT, J., ELLWART,J.and ISSELS, R., Heat-shock protein 72 on tumor cells: a recognition structure for natural-killer cells. J. Immunol, 1997. 158(9): p. 4341-4350.
10. MULTHOFF, G., BOTZLER, C.,WIESNET, M., EISSNER, G. and ISSELS, R., CD3 large granular lymphocytes recognize a heat-inducible immunogenic determinant associated with the 72-kD heat-shock protein on human sarcoma cells. Blood, 1995. 86(4): p. 1374-1382.
11. MULTHOFF, G.a.H., L.E., Cell-surface expression of heat-shock proteins and the immune response. Cell Stress Chaperones, 1996. 1(3): p. 167-176.
12. Febbraio MA, O.P., Nielsen HB, Steensberg A, Keller C, Krustrup P, Secher NH, Pedersen BK., Exercise induces hepatosplanchnic release of heat shock protein 72 in humans. J. Physiol. , 2002. 544(3): p. 957-962.
13. Fleshner, M., Campisi, J., Amiri, L., and Diamond, D. M, Cat exposure induces both intra- and extracellular Hsp72: the role of adrenal hormones. Psychoneuroendocrinology, 2004. 29(9): p. 1142-1152.
14. Williams RS, B.I., Protective responses in the ischemic myocardium. J Clin Invest 2000. 106(7): p. 813-818.
15. Wright BH, C.J., El-Nahas AM, Wood RF, Pockley AG., Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease. Heart Vessels, 2000. 15(1): p. 18-22.
16. Bobryshev YV, L.R., Expression of heat shock protein-70 by dendritic cells in the arterial intima and its potential significance in atherogenesis. J Vasc Surg 2002. 35: p. 368-375.
17. Pockley AG, G.A., Thulin T, et al, Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension Hypertension, 2003. 42(3): p. 235-8.
18. Chan YC, S.N., Abdus Samee-M, Berwanger CS, Stanford J, Singh M, Mansfield AO, Stansby G,, Anti-heat-shock protein 70 kDa antibodies in vascular patients. Eur J Vasc Endovasc Surg 1999. 18: p. 381-385.
19. Yuan, J., et al., Plasma antibodies to heat shock protein 60 and heat shock protein 70 are associated with increased risk of electrocardiograph abnormalities in automobile workers exposed to noise. Cell Stress Chaperones, 2005. 10(2): p. 126-35.
20. Zhu J, Q.A., Wu H, et al, Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease. Arterioscler Thromb Vasc Biol, 2003. 23(6): p. 1055-1059.
21. Sharma M, G.N., Chaturvedi G, et al, A possible role of HSP70 in mediating cardioprotection in patients undergoing CABG. Mol Cell Biochem, 2003. 247(1-2): p. 32-36.
22. Herz I, R.R., Roth A, et al, Serum levels of anti heat shock protein 70 antibodies in patients with stable and unstable angina pectoris. Acute Card Care, 2006. 8(1): p. 46-50.
23. Kocsis J, V.A., Vatay A, Duba J, Karádi I, Füst G, Prohászka Z., Antibodies against the human heat shock protein hsp70 in patients with severe coronary artery disease. Immunol Invest, 2002. 31(3-4): p. 219-231.
24. Pockley AG, S.J., Corton JM, Detection of heat shock protein 70 and anti-Hsp70 antibodies in the serum of normal individuals. Immunol Invest, 1998. 27(6): p. 367-377.
25. AG, P., Heat shock proteins in health and disease: therapeutic targets or therapeutic agents. Exp Rev Mol Med, 2001. 3(21): p. 1-21.
26. Dybdahl, B., et al., Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart, 2005. 91(3): p. 299-304.
27. Dart AM, C.J., Lipids and the endothelium Cardiovasc Res, 1999. 43(2): p. 308-322.
28. R, R., The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature, 1993. 362(6423): p. 801-809.
29. Peng-Yuan Yang, Y.-C.R., Ling Lu, et al. , Time courses of vascular endothelial growth factor and intercellular adhesion molecule-1 expressions in aortas of atherosclerotic rats. Life Sciences, 2005. 77: p. 2529-2539.
30. Bennani NK, K.L., Bouayadi FE, et al., New model of atherosclerosis in insulin resistant sand rats:hypercholesterolemia combined with D2 vitamin. Atherosclerosis, 2000. 150: p. 55-61.
31. Cai GJ, M.C., Xie HH , LU LH, SU DF, , Arterial baroreflex dysfunction promotes atherosclerosis in rats. Atherosclerosis, 2005. 183: p. 41047.
32. CC., H., Pathogenesis of atherosclerosis: State of the art Cardiovasc Drugs Ther. , 1990. 4(Suppl 5): p. 993-1004.
33. Lamarche B, L.G., Atherosclerosis prevention for the next decade:risk assessment beyond low density lipoprotein cholesterol. Can J Cardiol, 1998. 14: p. 841-851.
34. Kusterer K, P.T., Fortmeyer HP, et al. , Chronic selective hypertriglyceridemia impairs endothelium dependent vasodilatation in rats. Cardiovasc Res J, 1999. 42:: p. 783-793.
35. Kocsis, J., et al., Antibodies against the human heat shock protein hsp70 in patients with severe coronary artery disease. Immunol Invest, 2002. 31(3-4): p. 219-31.
36. Gerner C, V.S., Gelbmann D, et al. , Concomitant determination of absolute values of cellular protein amounts, synthesis rates, and turnover rates by quantitative proteomeprofiling. . Mol Cell Proteomics., Jul 2002. 1(9): p. 528-537.
37.萨姆布鲁克J,拉.D.著.,黄培堂译. ,分子克隆实验指南. . Vol.第三版. 2002:北京:科学技术出版社.
38. Wick G, K.M., Xu Q, Autoimmune and inflammatory mechanisms in atherosclerosis. Ann Rev Immunol 2004. 22: p. 361-403.
39. Young DB, M.A., Smith DF., Stress proteins and infectious disease. Cold Spring Harbor, NY: Cold Spring Harbor Press, 1990. 8: p. 131-65.
40. Kaufmann SHE, S.B., Heat shock protein antigens in immunity against infection and self. . Cold Spring Harbor, NY: Cold Spring Harbor Press,, 1994: p. 495-531.
41. Chan, Y.C., et al., Anti-heat-shock protein 70 kDa antibodies in vascular patients. Eur J Vasc Endovasc Surg, 1999. 18(5): p. 381-5.
42. Sims, T.J., et al., Serum IgG to heat shock proteins and Porphyromonas gingivalis antigens in diabetic patients with periodontitis. J Clin Periodontol, 2002. 29(6): p. 551-62.
43. Portig, I., S. Pankuweit, and B. Maisch, Antibodies against stress proteins in sera of patients with dilated cardiomyopathy. J Mol Cell Cardiol, 1997. 29(8): p. 2245-51.
44. Pockley, A.G., et al., Circulating heat shock protein and heat shock protein antibody levels in established hypertension. J Hypertens, 2002. 20(9): p. 1815-20.
45. Wright, B.H., et al., Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease. Heart Vessels, 2000. 15(1): p. 18-22.
46. Figueredo A, I.J., Rodriguez A, Molino AM, Gomez-de la Concha E, Fernandez-Cruz A, Pati?o R, Increased Serum Levels of IgA Antibodies to HSP70 Protein in Patients with Diabetes Mellitus: Their Relationship with Vascular Complications. Clinical Immunology and Immunopathology, 1996. 79: p. 252-255.
47. Pockley AG, F.J., Heat shock proteins in cardiovascular disease and the prognostic value of heat shock protein related measurements. Heart 2005. 91(9): p. 1124-1126.
48. Wu, T. and R.M. Tanguay, Antibodies against heat shock proteins in environmental stresses and diseases: friend or foe? Cell Stress Chaperones, 2006. 11(1): p. 1-12.
49. Kramer J, H.P., Prohaszka Z, et al. , Frequencies of certain complement protein alleles and serum levels of anti-heat-shock protein antibodies in cerebrovascular diseases. Stroke, 2000. 31(11): p. 2648-2652.
50. Bonorin C, N.N., Zhang X, et al. , Characteristics of the strong antibody response to mycobacterial Hsp70: a primary, T-cell dependent IgG response with no evidence of natural priming orγδT cell involvement. . J Immunol, 1998. 161: p. 5220-16.
51. Madamanchi NR, L.S., Patterson C, Runge MS., Reactive oxygen species regulate heat-shock protein 70 via the JAK/STAT pathway. . Arterioscler Thromb Vasc Biol. , 2001. 21(3): p. 321-6.
52. Vogt, S., et al., Detection of anti-hsp70 immunoglobulin G antibodies indicates better outcome in coronary artery bypass grafting patients suffering from severe preoperative angina. Ann Thorac Surg, 2004. 78(3): p. 883-9; discussion 889.
53. Herz, I., et al., Serum levels of anti heat shock protein 70 antibodies in patients with stable and unstable angina pectoris. Acute Card Care, 2006. 8(1): p. 46-50.
54. Jacob George, S.G., Iris Barshack, Madhavir Singh, Sara Pri-Chen, Shlomo Laniado, Gad Keren, , Accelerated Intimal Thickening in Carotid Arteries of Balloon-Injured RatsAfter Immunization Against Heat Shock Protein 70. JACC, 2001. 38(5): p. 1564-9.
55. Jonasson L, H.J., Skalli O, Bondjers G, Hansson GK,, Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986. 6(2): p. 131-138.
56. Hansson GK, H.J., Jonasson L, Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol, 1989. 135(1): p. 169-175.
57. Georgios Foteinos, A.R.A., Kaushik Mandal, Marjan Jahangiri and Qingbo Xu Anti–Heat Shock Protein 60 Autoantibodies Induce Atherosclerosis in Apolipoprotein E–Deficient Mice via Endothelial Damage. Circulation, 2005: p. 1206-1213
58. Mayr M, M.B., Kiechl S, et al., Endothelial cytotoxicity mediated by serum antibodies to heat shock proteins of Escherichia coli and Chlamydia pneumoniae: immune reactions to heat shock proteins as a possible link between infection and atherosclerosis. Circulation, 1999. 99: p. 1560-1566.
59. Park CW, K.J., Lee JH, Kim YS, Ahn HJ, Shin YS, Kim SY, Choi EJ, Chang YS, Bang BK., High glucose-induced intercellular adhesion molecule-1 (ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-kappa B-dependent. Diabetologia, 2000. 43(12): p. 1544-1553.
60. Woo CW, S.Y., O K., Homocysteine Induces Monocyte Chemoattractant Protein-1 Expression in Hepatocytes Mediated via Activator Protein-1 Activation. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 2008. 283(3): p. 1282-1292.
61. Singh B, G.R., Expression of human 60-kD heat shock protein (HSP60 or P1) in Escherichia coli and the development and characterization of corresponding monoclonal antibodies. DNA Cell Biol, 1992. 11(6): p. 489-96.
62. Zhu, J., et al., Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease. Arterioscler Thromb Vasc Biol, 2003. 23(6): p. 1055-9.
63. Rosenfeld ME, P.W., YlS-Herttuala S, Butler S, Witztum JL, Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis., 1990. 10(3): p. 336-349.
64. Salonen JT, Y.-H.S., Yamamoto R, Butler S, Korpela H, Salonen R, Nyyssonen K, Palinski W, Witztum JL. , Increased autoantibody titer to an epitope of oxidized LDL predicts progression of carotid atherosclerosis. Lancet., 1992. 339: p. 883-887.
65. Yla-Herttuala S, P.W., Rosenfeld ME, Parthasarathy S, Carew TE, Butler S, et al., Evidence for the presence of oxidatively modified LDL in atherosclerotic lesions of rabbits and man. J Clin Invest 1989. 84(4): p. 1086-1095.
66. Agnieszka Krupa, H.K., Michael A. Matthay, and Anna K. Kurdowska, Proin?ammatory activity of anti-IL-8 autoantibody:IL-8 complexes in alveolar edema ?uid from patients with acute lung injury. . Am J Physiol Lung Cell Mol Physiol, 2004. 286: p. L1105-L1113.
67. Ravetch JV, B.S., IgG Fc receptors. Annu Rev Immunol., 2001. 19: p. 275-290.
68. Jewon Ryu, C.W.L., Jin-Ae Shin, Chan-Sik Park, Jae Joong Kim, Seung-Jung Park, Ki Hoon Han FcγRIIa mediates C-reactive protein-induced inflammatory responses of human vascular smooth muscle cells by activating NADPH oxidase 4. Cardiovascular Research, 2007. 75(3): p. 555-565.
69. Pfeiffer JR, H.P., Waters MA, Hynes ML, Schnurr PP, Demidenko E, Bech FR,Morganelli PM, Levels of expression of Fcgamma receptor IIA (CD32) are decreased on peripheral blood monocytes in patients with severe atherosclerosis. Atherosclerosis, 2001. 155(1): p. 211-218.
70. Masuda M, T.H., Increase of soluble Fc gamma RIIIa derived from macrophages in plasma from patients with atherosclerosis. Rinsho Byori, 2002. 50(5): p. 502-505.
71. Ratcliffe NR, K.S., Morganelli PM., Immunocytochemical detection of Fcgamma receptors in human atherosclerotic lesions. Immunol Lett, 2001. 77(3): p. 169-174.
72. Pfeiffer JR, H.P., Waters MA, Hynes ML, Schnurr PP, Demidenko E, Bech FR, Morganelli PM, Levels of expression of Fcgamma receptor IIA (CD32) are decreased on peripheral blood monocytes in patients with severe atherosclerosis. Atherosclerosis, 2001. 155(1): p. 211-218.
73. Ratcliffe NR, K.S., Morganelli PM, Immunocytochemical detection of Fcgamma receptors in human atherosclerotic lesions. Immunol Lett, 2001. 77(3): p. 169-174.
74. Hernández-Vargas P, O.-M.G., López-Franco O, Suzuki Y, Gallego-Delgado J, Sanjuán G, Lázaro A, López-Parra V, Ortega L, Egido J, Gómez-Guerrero C., FcγReceptor Deficiency Confers Protection Against Atherosclerosis in Apolipoprotein E Knockout Mice. Circulation Research, 2006. 99(11): p. 1188-1196.
75. Kwei S, S.G., Takahas M, Taylor G, Folkman MJ, Gimbrone MA Jr,Garcia-Cardena G, Early adaptive responses of the vascular wall during venous arterialization in mice. Am J Pathol, 2004. 164(1): p. 81- 89.
76. Kreisel D, K.A., Szeto WY, et al., A simple method for culturing mouse vascular endothelium. J Immunol Methods,, 2001. 254: p. 31-45.
77. Clayton, A., A. Turkes, H. Navabi, M. D. Mason, and Z. Tabi, Induction of heat shock proteins in B-cell exosomes. . J. Cell Sci, 2005. 118(Pt 16): p. 3631-3638.
78. Gastpar, R., M. Gehrmann, M. A. Bausero, A. Asea, C. Gross, J. A. Schroeder, and G. Multhoff, Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res, 2005. 65: p. 5238-5247.
79. Altin, J.G., and E. B. Pagler. , A one-step procedure for biotinylation and chemical cross-linking of lymphocyte surface and intracellular membrane-associated molecules. . Anal. Biochem., 1995. 224(1): p. 382-389.
80. Jilrgens, G., Q. Xu, L. A. Huber, G. Bock, H. Howanietz, G. Wick, K. N. Traill. , Promotion of lymphocyte growth by high density lipoproteins (HDL): physiological significance of the HDL binding site. J. Biol. Chem., 1989. 264(15): p. 8549-8556.
81. Nagarajan S, V.K., Anderson M, Sayed U, Zhu C, Selvaraj P. , Nagarajan S, Venkiteswaran K, Anderson M, Sayed U, Zhu C, Selvaraj P. Cell specific, activation dependent regulation of neutrophil CD32A ligand binding function. . Blood, 2000. 95: p. 1069-77.
82. Stewart BW, N.S., Recombinant CD36 inhibits OxLDL-induced ICAM-1 - dependent monocyte adhesion. Mol Immunol 2006. 43(3): p. 255-67.
83. Jane Winer Christopher Kwang S. Jung, I.S., et al. , Development and Validation of Real-Time Quantitative Reverse Transcriptase-Polymerase Chain Reaction for Monitoring Gene Expression in Cardiac Myocytes in Vitro Analytical Biochemistry,, 1999. 270: p. 41-49.
84. Methods, T.D.S.e.a.Q.R.T.-P.C.R.t.S.m.D.C.o.E.a.R.-T., Quantitative ReverseTranscription-Polymerase Chain Reaction to Study mRNA Decay: Comparison of Endpoint and Real-Time Methods. Analytical Biochemistry, 2000. 285: p. 194-204.
85. Ross, R., Atherosclerosis-an in?ammatory disease. N. Engl. J. Med, 1999. 340: p. 115-126.
86. Lindner V, F.J., Reidy MA, , Mouse model of arterial injury. Circ Res 1993. 73: p. 792-796.
87. Li J, H.S., Guo ZG., Platelet-derived growth factor stimulated vascular muscle cell proliferation and its molecular mechanism. Acta Pharmacol Sin, 2000. 21(4): p. 340-344.
88. Jr, B.A., The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol., 1996. 14: p. 649-683.
89. Y, K.M.B.-N., Phosphorylation meets ubiquitination:the control of NF-kB activity. Ann Rev Immunol, 2000. 18: p. 621-663.
90. Schett G, X.Q., Amberger A, Van der Zee R, Recheis H, Willeit J, Wick G, Autoantibodies against Heat Shock Protein 60 Mediate Endothelial Cytotoxicity. J. Clin. Invest., 1995. 96: p. 2569-2577.
91. Cybulsky, M.I., and Gimbrone, M.A., Jr. , Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. . Science, 1991. 251: p. 788-791.
92. Johnson RC, C.S., Dong ZM, Ordovas JM, Mayadas TN, Herz J, Hynes RO, Schaefer EJ, Wagner DD., Absence of P-selectin delays fatty streak formation in mice. J. Clin. Invest, 1997. 99(5): p. 1037-1043.
93. Dong, Z.M., et al. , The combined role of P- and E-selectins in atherosclerosis. J. Clin. Invest, 1998. 102: p. 145-152.
94. Collins, R.G., et al., P-selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J. Exp. Med, 2000. 191: p. 189-194.
95. Dong, Z.M., Brown, A.A., and Wagner, D.D. , Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice. Circulation, 2000. 101: p. 2290-2295.
96. Boisvert, W.A., Santiago, R., Curtiss, L.K., and Terkeltaub, R.A., A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor deficient mice. J. Clin. Invest, 1998. 101(2): p. 353-363.
97. Boring, L., Gosling, J., Cleary, M., and Charo, I.F. , Decreased lesion formation in CCR2 -/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature, 1998. 394: p. 894-897.
98. Gu L, O.Y., Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ., Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol. Cell. , 1998. 2(2): p. 275-281.
99. JR., H., The role of MCP-1 in atherosclerosis. Stem Cells, 2000. 18(1): p. 65-6.
100. D, S., Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem 1997. 272: p. 20963-6.
101. Keaney JF Jr, G.Y., Cunningham D, et al. , Vascular incorporation of alpha-tocopherol prevents endothelial dysfunction due to oxidized LDL by inhibiting protein kinase Cstimulation. J Clin Invest, 1996. 98(2): p. 386-394.
102. Mehta A, Y.B., Khan S, et al, Oxidized low-density lipoproteins facilitate leukocyte adhesion to aortic intima without affecting endothelium-dependent relaxation: role of P-selectin. Arterioscler Thromb Vasc Biol, 1995. 15: p. 2076-2083.
103. Kleindienst R, X.Q., Willeit J, Waldenberger FR, Weimann S, Wick G., Immunology of atherosclerosis. Demonstration of heat shock protein 60 expression and T lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions. . Am J Pathol, 1993. 142(6): p. 1927-1937.
104. Han Z, T.Q., Park S, et al., Two Hsp70 family members expressed in atherosclerotic lesions. Proc Natl Acad Sci U S A, 2003. 100(3): p. 1256-1261.
105. Wick G, R.M., Amberger A, Metzler B, Mayr M, Falkensammer G, Xu Q., Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue. Faseb J, 1997. 11(13): p. 1199-1207.
106. Zhu W, R.P., Pellegatta F, Catapano AL., Oxidized-LDL induce the expression of heat shock protein 70 in human endothelial cells. Biochem. Biophys. Res. Commun., 1994. 200(1): p. 389-394.
107. Shin, B.K., Wang, H., Yim, A. M., Le, N. F., Brichory, F., Jang, J. H., Zhao, R., Puravs, E., Tra, J., Michael, C. W., Misek, D. E., Hanash, S. M., Global profiling of the cell surface proteome of cancer cells uncovers an abundance of proteins with chaperone function. J. Biol. Chem, 2003. 278: p. 7607-7616.
108. Virginia L. Vega, M.R.-S., Tiffany Frey, , Hsp70 Translocates into the Plasma Membrane after Stress and Is Released into the Extracellular Environment in a Membrane-Associated Form that Activates Macrophages. TheJournal of Immunology, 2008. 180(6): p. 4299-4307.
109. Botzler, C., Ellwart, J., Gunther, W., Eissner, G., Multhoff, G, Synergistic effects of heat and ET-18-OCH3 on membrane expression of hsp70 and lysis of leukemic K562 cells. Exp. Hematol, 1999. 27(3): p. 470-478.
110. Gehrmann M, P.K., Hutzler P, Gastpar R, Margulis B, Multhoff G., Effects of antineoplastic agents on cytoplasmic and membrane- bound heat shock protein 70 (Hsp70) levels. Biol. Chem, 2002. 383(11): p. 1715-1725.
111. Gehrmann, M., Brunner, M., Pfister, K., Reichle, A., Kremmer, E., Multhoff, G. , Differential up-regulation of cytosolic and membranebound heat shock protein 70 in tumor cells by anti-inflammatory drugs. Clin. Cancer Res, 2004. 10(10): p. 3354-3363.
112. Arispe, N., M. Doh, and A. De Maio. , Lipid interaction differentiates the constitutve and stress-induced heat shock proteins Hsc70 and Hsp70. Cell Stress Chaperones 2002. 7(4): p. 330-338.
113. Zhan R, L.X., Liu X, Wang X, Gong J, Yan L, Wang L, Wang Y, Wang X, Qian LJ., Heat shock protein 70 is secreted from endothelial cells by a non-classical pathway involving exosomes. Biochem Biophys Res Commun, 2009. 387(2): p. 229-33.
114. Dybdahl B, S.S., Waage A, et al. , Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart, 2005. 91(3): p. 299-304.
115. Mamoru S, Y.S., Tomonari A, et al. , Elevated circulating levels of heat shock protein 70 are related to systemic inflammatory reaction through monocyte Toll signal in patientswith heart failure after acute myocardial infarction. Europ J Heart Failure, 2006. 8: p. 810-815.
116. Seifert PS, M.M., Roth I, Bhakdi S., Analysis of complement C3 activation products in human atherosclerotic lesions. Atherosclerosis, 1991. 91(1-2): p. 155-62.
117. Pang AS, K.A., Minta JO., C3 deposition in cholesterol-induced atherosclerosis in rabbits: a possible etiologic role for complement in atherogenesis. J Immunol., 1979. 123(3): p. 1117-22.
118. Buono C, C.C., Witztum JL, Maguire GF, Connelly PW, Carroll M, Lichtman AH., Influence of C3 deficiency on atherosclerosis. Circulation, 2002. 105(25): p. 3025-31.
119. Ravetch JV, K.J.-P., Fc Receptors. Annu Rev Immunol 1991. 9: p. 457-92.
120. Unkeless JC, S.Z., Lin C, DeBeus E., Function of human Fc gamma RIIA and Fc gamma RIIIB. Semin Immunol 1995. 7(1): p. 37-44.
121. Wang, Y., C. G. Kelly, J. T. Kartunen, T. Whittall, P. J. Lehner, L. Duncan, P. MacAry, J. S. Younson, M. Singh, W. Oehlmann, et al. , CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC chemokines. Immunity, 2001. 15(971-983).
122. Wang, Y., C. G. Kelly, M. Singh, E. G. McGowan, A.-S. Carrara, L. A. Bergmeier, and T. Lehner. , Stimulation of Th1-polarizing cytokines, C-C chemokines, maturation of dendritic cells and adjuvant function by the peptide binding fragment of heat shock protein 70. . J. Immunol. , 2002. 169: p. 2422-2429.
123. Whittall, T., Y. Wang, J. Younson, C. Kelly, L. Bergmeier, B. Peters, M. Singh, and T. Lehner. , Interaction between the CCR5 chemokine receptors and microbial HSP70. . J. Immunol. , 2006. 36: p. 2304-2314.
124. Ahn, H.Y., Hadizadeh, K. R., Seul, C., Yun, Y. P., Vetter, H., and Sachinidis, A, Epigallocathechin-3 gallate selectively inhibits the PDGF-BB-induced intracellular signaling transduction pathway in vascular smooth muscle cells and inhibits transformation of sis-transfected NIH 3T3 fibroblasts and human glioblastoma cells (A172). . Mol. Biol. Cell., 1999. 10(4): p. 1093-1104.
125. Akishita, M., Ito, M., Lehtonen, J. Y., Daviet, L., Dzau, V. J., and Horiuchi, M., Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and in?uences fetal vascular growth. J. Clin. Invest. , 1999. 103: p. 63-71.
126. Ledebur HC, P.T., Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells. Essential roles of a variant NF-kappa B site and p65 homodimers. J. Biol. Chem., 1995. 270(2): p. 933-943.
127. Wrighton, C.J., Hofer-Warbinek, R., Moll, T., Eytner, R., Bach, F. H., and de Martin, R., xxxxxx. J. Exp. Med. , 1996 183: p. 1013-1022.
128. Boyle, E.M., Jr., Kovacich, J. C., Canty, T. G., Jr., Morgan, E. N., Chi, E.,Verrier, E. D., and Pohlman, T. H., Inhibition of nuclear factor-kappa B nuclear localization reduces human E-selectin expression and the systemic inflammatory response. Circulation 1998. 98: p. 282-288.
129. Mulvany, M.J., and Aalkjaer, C., Structure and function of small arteries. . Physiol. Rev., 1990. 70: p. 921-961.
130. Nimmerjahn F, R.J., Fcgamma receptors: old friends and new family members. Immunity, 2006. 24(1): p. 19-28.
131. Hazenbos WL, H.I., Meyer D, Hofhuis FM, Renardel de Lavalette CR, Schmidt RE, Capel PJ, van de Winkel JG, Gessner JE, van den Berg TK, Verbeek JS., Murine IgG1 complexes trigger immune effector functions predominantly via Fc gamma RIII (CD16). Immunol. , 1998. 161(6): p. 3026-32.
132. Auwardt RB, M.S., Chen CG, Power DA., Regulation of nuclear factor kappaB by corticosteroids in rat mesangial cells. J Am Soc Nephrol, 1998. 9(9): p. 1620-1628.
133. Martin-Ventura JL, B.-C.L., Munoz-Garcia B, Gomez Hernandez A, Arribas A, Ortega L, Tunon J, Egido J. , NF-kappaB activation and Fas ligand overexpression in blood and plaques of patients with carotid atherosclerosis: potential implication in plaque instability. Stroke, 2004. 35(2): p. 458-463.
134. Hernandez-Presa M, B.C., Ortego M, Tunon J, Renedo G, Ruiz Ortega M, Egido J., Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation, 1997. 95(6): p. 1532-1541.
135. Monaco C, A.E., Kiriakidis S, Mauri C, Bicknell C, Foxwell B, Cheshire N, Paleolog E, Feldmann M, Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis. Proc Natl Acad Sci USA, 2004. 101(15): p. 5634-5639.
136. Brand K, P.S., Rogler G, Bartsch A, Brandl R, Knuechel R, Page M, Kaltschmidt C, Baeuerle PA, Neumeier D., Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest, 1996. 97(7): p. 1715-1722.
137. Masuda M, T.H., Increase of soluble Fc gamma RIIIa derived from macrophages in plasma from patients with atherosclerosis. Rinsho Byori, 2002. 50(5): p. 502-505.
138. Daeron, M., Fc receptor biology. Annu. Rev. Immunol., 1997. 15: p. 203-234.
139. Gessner, J.E., H. Heiken, A. Tamm, and R. E. Schmidt. , The IgG Fc receptor family. . Ann. Hematol., 1998. 76 p. 231-248.
140. Ravetch, J.V., Fc receptors. Curr. Opin. Immunol. , 1997. 9: p. 121-125.
141. Majid Ghayour-Mobarhan, David J. Lamb, Shima Tavallaie, Gordon A. A. Ferns. Relationship between plasma cholesterol, von Willebrand factor concentrations, extent of atherosclerosis and antibody titres to heat shock proteins-60, -65 and -70 in cholesterol-fed rabbits. Int. J. Exp. Path..2007.8: 249-255.
1. R., R., The pathogenesis of atherosclerosis: a perspective for the 1990s. . Nature 1993. 362(6423): p. 801-9.
2. R., R., Atherosclerosis—an inflammatory disease. . N EnglJ Med 1999. 340(2): p. 115-26.
3. Libby P, R.P., Maseri A., Inflammation and atherosclerosis. . Circulation 2002. 105(9): p. 1135-43.
4. GK., H., Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001. 21(12): p. 1876-90.
5. Wick G, X.Q.A.a.a.d.-. and e.E.G.–66., Atherosclerosis—an autoimmune disease. . Exp Gerontol, 1999. 34(4): p. 559-66.
6. Xu QB, e.a., Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks, and atherosclerotic plaques in young and aged human specimens. . Clin Immunol Immunopathol 1990. 56(3): p. 344-59.
7. RI., M., Cells in stress: transcriptional activation of heat shock genes. Science 1993. 259(5100): p. 1409-10.
8. Patterson C, C.D., Welcome to the machine: a cardiologist’s introduction toprotein folding and degradation. Circulation 2002. 106(21).
9. Xu Q, W.G., The role of heat shock proteins in protection and pathophysiology of the arterial wall. . Mol Med Today 1996. 2(9): p. 372-9.
10. Benjamin IJ, M.D., Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease. Circ Res 1998. 83(2): p. 117-32.
11. AG., P., Heat shock proteins, inflammation, and cardiovascular disease. 105, 2002. 8(1012-7).
12. Wick G, P.H., Millonig G. , Atherosclerosis as an autoimmune disease: an update. . Trends Immunol, 2001. 22(12): p. 665-9.
13. Q., X., Arterioscler Thromb Vasc Biol Arterioscler Thromb Vasc Biol 2002. 22: p. 1547-59.
14. J.L. Brodsky, Post-translational translocation: not all Hsc70s are created equal. Trends Biochem. , 1996. 21: p. 122-126.
15. Zhu Jianhui , e.a., Association of Serum Antibodies to Heat-Shock Protein 65 With Coronary Calcification Levels: Suggestion of Pathogen-Triggered Autoimmunity in Early Atherosclerosis. Circulation, 2004. 109: p. 36-41.
16. Asea A, K.S., Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, et al. , HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. . Nat Med 2000. 6(4): p. 435-42.
17. Pockley AG, G.A., Thulin T, et al, Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension Hypertension, 2003. 42(3): p. 235-8.
18. Jacob George, S.G., Iris Barshack, Madhavir Singh, Sara Pri-Chen, Shlomo Laniado, Gad Keren, , Accelerated Intimal Thickening in Carotid Arteries of Balloon-Injured Rats After Immunization Against Heat Shock Protein 70. JACC, 2001. 38(5): p. 1564-9.
19. Young RA, E.T., Stress proteins, infection, and immune surveillance. Cell, 1989. 59(1): p. 5-8.
[1]邓红艳,廖丽娅,张雨,等. 2型糖尿病患者亚临床动脉粥样硬化与胰岛素抵抗[J].临床心血管病杂志,2007,23(4):265-266.
[2] Frosteg?rd Alan G. Pockley, Anastasia Georgiades A, et al.Serum Heat Shock Protein 70 Levels Predict the Development of Atherosclerosis in Subjects With Established Hypertension. Hypertension 2003,42:235-238.
[3]魏蒙,顾水明,张昀昀,等.普伐他汀福辛普利及合用对大鼠心肌梗死后肿瘤坏死因子-表达及心室重构的影响[J].中华心血管病杂志,2005,33(5):444-447.
[4]邹继红,史兆荣.老年2型糖尿病脂联素和C反应蛋白与动脉粥样硬化的关系[J].中华老年心脑血管病杂志, 2007 ,9(9):599-601.
[5] Ghayour-Mobarhan M,Lamb D J, Tavallaie S,et al. Relationship between plasma cholesterol, von Willebrand factor concentrations, extent of atherosclerosis and antibody titres to heat shock proteins-60, -65 and -70 in cholesterol-fed rabbits[J]. Int J Exp Path, 2007, 88(4):249–255.
[6] Wu T Ch,Ma J X, Chen Sh,et al. Association of plasma antibodies against the inducible Hsp70 with hypertension and harsh working conditions[J]. Cell Stress Chaperones,2001,6(4):394-401.
[7] Kim Y K, Suarez J,Hu Y,et al. Deletion of the Inducible 70-kDa Heat Shock Protein Genes in Mice Impairs Cardiac Contractile Function and Calcium Handling Associated With Hypertrophy[J]. Circulation,2006,113(5):2589-2597.
[8] Gross C,Hansch D,Gastpar R,et al . Interaction of Heat Shock Protein 70 Peptide with NK Cells Involves the NK Receptor CD94[J]. Biological chemistry ,2003,384(12):267– 279.
[9] Xu Q B. Role of Heat Shock Proteins in Atherosclerosis[R]. Arterioscler Thromb Vasc Biol.1547-1559.
2. P, L., Inflammation in atherosclerosis. Nature 2002. 420: p. 868-874.
3. Hansson GK, B.G., Bylock A, Hjalmarsson L., Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol, 2001. 21: p. 1876-1890.
4. Wick G, X.Q., Atherosclerosis--an autoimmune disease! Exp Gerontol, 1999. 34(4): p. 559-566.
5. Ritossa, F., A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia, 1962: p. 571-573.
6. Tissieres, A., Mitchell HK, Tracy UM, Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs. J Mol Bio, 1974. 84(3): p. 389-398.
7. Lindquist S, C.E., The heat shock proteins. Annu Rev Genet, , 1988. 22: p. 631-677.
8. Multhoff G, B.C., Wiesnet M, Müller E, Meier T, Wilmanns W, Issels RD., A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. Int J Cancer 1995. 61(2): p. 272-9.
9. MULTHOFF, G., BOTZLER, C., JENNEN, L., SCHMIDT, J., ELLWART,J.and ISSELS, R., Heat-shock protein 72 on tumor cells: a recognition structure for natural-killer cells. J. Immunol, 1997. 158(9): p. 4341-4350.
10. MULTHOFF, G., BOTZLER, C.,WIESNET, M., EISSNER, G. and ISSELS, R., CD3 large granular lymphocytes recognize a heat-inducible immunogenic determinant associated with the 72-kD heat-shock protein on human sarcoma cells. Blood, 1995. 86(4): p. 1374-1382.
11. MULTHOFF, G.a.H., L.E., Cell-surface expression of heat-shock proteins and the immune response. Cell Stress Chaperones, 1996. 1(3): p. 167-176.
12. Febbraio MA, O.P., Nielsen HB, Steensberg A, Keller C, Krustrup P, Secher NH, Pedersen BK., Exercise induces hepatosplanchnic release of heat shock protein 72 in humans. J. Physiol. , 2002. 544(3): p. 957-962.
13. Fleshner, M., Campisi, J., Amiri, L., and Diamond, D. M, Cat exposure induces both intra- and extracellular Hsp72: the role of adrenal hormones. Psychoneuroendocrinology, 2004. 29(9): p. 1142-1152.
14. Williams RS, B.I., Protective responses in the ischemic myocardium. J Clin Invest 2000. 106(7): p. 813-818.
15. Wright BH, C.J., El-Nahas AM, Wood RF, Pockley AG., Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease. Heart Vessels, 2000. 15(1): p. 18-22.
16. Bobryshev YV, L.R., Expression of heat shock protein-70 by dendritic cells in the arterial intima and its potential significance in atherogenesis. J Vasc Surg 2002. 35: p. 368-375.
17. Pockley AG, G.A., Thulin T, et al, Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension Hypertension, 2003. 42(3): p. 235-8.
18. Chan YC, S.N., Abdus Samee-M, Berwanger CS, Stanford J, Singh M, Mansfield AO, Stansby G,, Anti-heat-shock protein 70 kDa antibodies in vascular patients. Eur J Vasc Endovasc Surg 1999. 18: p. 381-385.
19. Yuan, J., et al., Plasma antibodies to heat shock protein 60 and heat shock protein 70 are associated with increased risk of electrocardiograph abnormalities in automobile workers exposed to noise. Cell Stress Chaperones, 2005. 10(2): p. 126-35.
20. Zhu J, Q.A., Wu H, et al, Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease. Arterioscler Thromb Vasc Biol, 2003. 23(6): p. 1055-1059.
21. Sharma M, G.N., Chaturvedi G, et al, A possible role of HSP70 in mediating cardioprotection in patients undergoing CABG. Mol Cell Biochem, 2003. 247(1-2): p. 32-36.
22. Herz I, R.R., Roth A, et al, Serum levels of anti heat shock protein 70 antibodies in patients with stable and unstable angina pectoris. Acute Card Care, 2006. 8(1): p. 46-50.
23. Kocsis J, V.A., Vatay A, Duba J, Karádi I, Füst G, Prohászka Z., Antibodies against the human heat shock protein hsp70 in patients with severe coronary artery disease. Immunol Invest, 2002. 31(3-4): p. 219-231.
24. Pockley AG, S.J., Corton JM, Detection of heat shock protein 70 and anti-Hsp70 antibodies in the serum of normal individuals. Immunol Invest, 1998. 27(6): p. 367-377.
25. AG, P., Heat shock proteins in health and disease: therapeutic targets or therapeutic agents. Exp Rev Mol Med, 2001. 3(21): p. 1-21.
26. Dybdahl, B., et al., Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart, 2005. 91(3): p. 299-304.
27. Dart AM, C.J., Lipids and the endothelium Cardiovasc Res, 1999. 43(2): p. 308-322.
28. R, R., The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature, 1993. 362(6423): p. 801-809.
29. Peng-Yuan Yang, Y.-C.R., Ling Lu, et al. , Time courses of vascular endothelial growth factor and intercellular adhesion molecule-1 expressions in aortas of atherosclerotic rats. Life Sciences, 2005. 77: p. 2529-2539.
30. Bennani NK, K.L., Bouayadi FE, et al., New model of atherosclerosis in insulin resistant sand rats:hypercholesterolemia combined with D2 vitamin. Atherosclerosis, 2000. 150: p. 55-61.
31. Cai GJ, M.C., Xie HH , LU LH, SU DF, , Arterial baroreflex dysfunction promotes atherosclerosis in rats. Atherosclerosis, 2005. 183: p. 41047.
32. CC., H., Pathogenesis of atherosclerosis: State of the art Cardiovasc Drugs Ther. , 1990. 4(Suppl 5): p. 993-1004.
33. Lamarche B, L.G., Atherosclerosis prevention for the next decade:risk assessment beyond low density lipoprotein cholesterol. Can J Cardiol, 1998. 14: p. 841-851.
34. Kusterer K, P.T., Fortmeyer HP, et al. , Chronic selective hypertriglyceridemia impairs endothelium dependent vasodilatation in rats. Cardiovasc Res J, 1999. 42:: p. 783-793.
35. Kocsis, J., et al., Antibodies against the human heat shock protein hsp70 in patients with severe coronary artery disease. Immunol Invest, 2002. 31(3-4): p. 219-31.
36. Gerner C, V.S., Gelbmann D, et al. , Concomitant determination of absolute values of cellular protein amounts, synthesis rates, and turnover rates by quantitative proteomeprofiling. . Mol Cell Proteomics., Jul 2002. 1(9): p. 528-537.
37.萨姆布鲁克J,拉.D.著.,黄培堂译. ,分子克隆实验指南. . Vol.第三版. 2002:北京:科学技术出版社.
38. Wick G, K.M., Xu Q, Autoimmune and inflammatory mechanisms in atherosclerosis. Ann Rev Immunol 2004. 22: p. 361-403.
39. Young DB, M.A., Smith DF., Stress proteins and infectious disease. Cold Spring Harbor, NY: Cold Spring Harbor Press, 1990. 8: p. 131-65.
40. Kaufmann SHE, S.B., Heat shock protein antigens in immunity against infection and self. . Cold Spring Harbor, NY: Cold Spring Harbor Press,, 1994: p. 495-531.
41. Chan, Y.C., et al., Anti-heat-shock protein 70 kDa antibodies in vascular patients. Eur J Vasc Endovasc Surg, 1999. 18(5): p. 381-5.
42. Sims, T.J., et al., Serum IgG to heat shock proteins and Porphyromonas gingivalis antigens in diabetic patients with periodontitis. J Clin Periodontol, 2002. 29(6): p. 551-62.
43. Portig, I., S. Pankuweit, and B. Maisch, Antibodies against stress proteins in sera of patients with dilated cardiomyopathy. J Mol Cell Cardiol, 1997. 29(8): p. 2245-51.
44. Pockley, A.G., et al., Circulating heat shock protein and heat shock protein antibody levels in established hypertension. J Hypertens, 2002. 20(9): p. 1815-20.
45. Wright, B.H., et al., Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease. Heart Vessels, 2000. 15(1): p. 18-22.
46. Figueredo A, I.J., Rodriguez A, Molino AM, Gomez-de la Concha E, Fernandez-Cruz A, Pati?o R, Increased Serum Levels of IgA Antibodies to HSP70 Protein in Patients with Diabetes Mellitus: Their Relationship with Vascular Complications. Clinical Immunology and Immunopathology, 1996. 79: p. 252-255.
47. Pockley AG, F.J., Heat shock proteins in cardiovascular disease and the prognostic value of heat shock protein related measurements. Heart 2005. 91(9): p. 1124-1126.
48. Wu, T. and R.M. Tanguay, Antibodies against heat shock proteins in environmental stresses and diseases: friend or foe? Cell Stress Chaperones, 2006. 11(1): p. 1-12.
49. Kramer J, H.P., Prohaszka Z, et al. , Frequencies of certain complement protein alleles and serum levels of anti-heat-shock protein antibodies in cerebrovascular diseases. Stroke, 2000. 31(11): p. 2648-2652.
50. Bonorin C, N.N., Zhang X, et al. , Characteristics of the strong antibody response to mycobacterial Hsp70: a primary, T-cell dependent IgG response with no evidence of natural priming orγδT cell involvement. . J Immunol, 1998. 161: p. 5220-16.
51. Madamanchi NR, L.S., Patterson C, Runge MS., Reactive oxygen species regulate heat-shock protein 70 via the JAK/STAT pathway. . Arterioscler Thromb Vasc Biol. , 2001. 21(3): p. 321-6.
52. Vogt, S., et al., Detection of anti-hsp70 immunoglobulin G antibodies indicates better outcome in coronary artery bypass grafting patients suffering from severe preoperative angina. Ann Thorac Surg, 2004. 78(3): p. 883-9; discussion 889.
53. Herz, I., et al., Serum levels of anti heat shock protein 70 antibodies in patients with stable and unstable angina pectoris. Acute Card Care, 2006. 8(1): p. 46-50.
54. Jacob George, S.G., Iris Barshack, Madhavir Singh, Sara Pri-Chen, Shlomo Laniado, Gad Keren, , Accelerated Intimal Thickening in Carotid Arteries of Balloon-Injured RatsAfter Immunization Against Heat Shock Protein 70. JACC, 2001. 38(5): p. 1564-9.
55. Jonasson L, H.J., Skalli O, Bondjers G, Hansson GK,, Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986. 6(2): p. 131-138.
56. Hansson GK, H.J., Jonasson L, Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol, 1989. 135(1): p. 169-175.
57. Georgios Foteinos, A.R.A., Kaushik Mandal, Marjan Jahangiri and Qingbo Xu Anti–Heat Shock Protein 60 Autoantibodies Induce Atherosclerosis in Apolipoprotein E–Deficient Mice via Endothelial Damage. Circulation, 2005: p. 1206-1213
58. Mayr M, M.B., Kiechl S, et al., Endothelial cytotoxicity mediated by serum antibodies to heat shock proteins of Escherichia coli and Chlamydia pneumoniae: immune reactions to heat shock proteins as a possible link between infection and atherosclerosis. Circulation, 1999. 99: p. 1560-1566.
59. Park CW, K.J., Lee JH, Kim YS, Ahn HJ, Shin YS, Kim SY, Choi EJ, Chang YS, Bang BK., High glucose-induced intercellular adhesion molecule-1 (ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-kappa B-dependent. Diabetologia, 2000. 43(12): p. 1544-1553.
60. Woo CW, S.Y., O K., Homocysteine Induces Monocyte Chemoattractant Protein-1 Expression in Hepatocytes Mediated via Activator Protein-1 Activation. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 2008. 283(3): p. 1282-1292.
61. Singh B, G.R., Expression of human 60-kD heat shock protein (HSP60 or P1) in Escherichia coli and the development and characterization of corresponding monoclonal antibodies. DNA Cell Biol, 1992. 11(6): p. 489-96.
62. Zhu, J., et al., Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease. Arterioscler Thromb Vasc Biol, 2003. 23(6): p. 1055-9.
63. Rosenfeld ME, P.W., YlS-Herttuala S, Butler S, Witztum JL, Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis., 1990. 10(3): p. 336-349.
64. Salonen JT, Y.-H.S., Yamamoto R, Butler S, Korpela H, Salonen R, Nyyssonen K, Palinski W, Witztum JL. , Increased autoantibody titer to an epitope of oxidized LDL predicts progression of carotid atherosclerosis. Lancet., 1992. 339: p. 883-887.
65. Yla-Herttuala S, P.W., Rosenfeld ME, Parthasarathy S, Carew TE, Butler S, et al., Evidence for the presence of oxidatively modified LDL in atherosclerotic lesions of rabbits and man. J Clin Invest 1989. 84(4): p. 1086-1095.
66. Agnieszka Krupa, H.K., Michael A. Matthay, and Anna K. Kurdowska, Proin?ammatory activity of anti-IL-8 autoantibody:IL-8 complexes in alveolar edema ?uid from patients with acute lung injury. . Am J Physiol Lung Cell Mol Physiol, 2004. 286: p. L1105-L1113.
67. Ravetch JV, B.S., IgG Fc receptors. Annu Rev Immunol., 2001. 19: p. 275-290.
68. Jewon Ryu, C.W.L., Jin-Ae Shin, Chan-Sik Park, Jae Joong Kim, Seung-Jung Park, Ki Hoon Han FcγRIIa mediates C-reactive protein-induced inflammatory responses of human vascular smooth muscle cells by activating NADPH oxidase 4. Cardiovascular Research, 2007. 75(3): p. 555-565.
69. Pfeiffer JR, H.P., Waters MA, Hynes ML, Schnurr PP, Demidenko E, Bech FR,Morganelli PM, Levels of expression of Fcgamma receptor IIA (CD32) are decreased on peripheral blood monocytes in patients with severe atherosclerosis. Atherosclerosis, 2001. 155(1): p. 211-218.
70. Masuda M, T.H., Increase of soluble Fc gamma RIIIa derived from macrophages in plasma from patients with atherosclerosis. Rinsho Byori, 2002. 50(5): p. 502-505.
71. Ratcliffe NR, K.S., Morganelli PM., Immunocytochemical detection of Fcgamma receptors in human atherosclerotic lesions. Immunol Lett, 2001. 77(3): p. 169-174.
72. Pfeiffer JR, H.P., Waters MA, Hynes ML, Schnurr PP, Demidenko E, Bech FR, Morganelli PM, Levels of expression of Fcgamma receptor IIA (CD32) are decreased on peripheral blood monocytes in patients with severe atherosclerosis. Atherosclerosis, 2001. 155(1): p. 211-218.
73. Ratcliffe NR, K.S., Morganelli PM, Immunocytochemical detection of Fcgamma receptors in human atherosclerotic lesions. Immunol Lett, 2001. 77(3): p. 169-174.
74. Hernández-Vargas P, O.-M.G., López-Franco O, Suzuki Y, Gallego-Delgado J, Sanjuán G, Lázaro A, López-Parra V, Ortega L, Egido J, Gómez-Guerrero C., FcγReceptor Deficiency Confers Protection Against Atherosclerosis in Apolipoprotein E Knockout Mice. Circulation Research, 2006. 99(11): p. 1188-1196.
75. Kwei S, S.G., Takahas M, Taylor G, Folkman MJ, Gimbrone MA Jr,Garcia-Cardena G, Early adaptive responses of the vascular wall during venous arterialization in mice. Am J Pathol, 2004. 164(1): p. 81- 89.
76. Kreisel D, K.A., Szeto WY, et al., A simple method for culturing mouse vascular endothelium. J Immunol Methods,, 2001. 254: p. 31-45.
77. Clayton, A., A. Turkes, H. Navabi, M. D. Mason, and Z. Tabi, Induction of heat shock proteins in B-cell exosomes. . J. Cell Sci, 2005. 118(Pt 16): p. 3631-3638.
78. Gastpar, R., M. Gehrmann, M. A. Bausero, A. Asea, C. Gross, J. A. Schroeder, and G. Multhoff, Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res, 2005. 65: p. 5238-5247.
79. Altin, J.G., and E. B. Pagler. , A one-step procedure for biotinylation and chemical cross-linking of lymphocyte surface and intracellular membrane-associated molecules. . Anal. Biochem., 1995. 224(1): p. 382-389.
80. Jilrgens, G., Q. Xu, L. A. Huber, G. Bock, H. Howanietz, G. Wick, K. N. Traill. , Promotion of lymphocyte growth by high density lipoproteins (HDL): physiological significance of the HDL binding site. J. Biol. Chem., 1989. 264(15): p. 8549-8556.
81. Nagarajan S, V.K., Anderson M, Sayed U, Zhu C, Selvaraj P. , Nagarajan S, Venkiteswaran K, Anderson M, Sayed U, Zhu C, Selvaraj P. Cell specific, activation dependent regulation of neutrophil CD32A ligand binding function. . Blood, 2000. 95: p. 1069-77.
82. Stewart BW, N.S., Recombinant CD36 inhibits OxLDL-induced ICAM-1 - dependent monocyte adhesion. Mol Immunol 2006. 43(3): p. 255-67.
83. Jane Winer Christopher Kwang S. Jung, I.S., et al. , Development and Validation of Real-Time Quantitative Reverse Transcriptase-Polymerase Chain Reaction for Monitoring Gene Expression in Cardiac Myocytes in Vitro Analytical Biochemistry,, 1999. 270: p. 41-49.
84. Methods, T.D.S.e.a.Q.R.T.-P.C.R.t.S.m.D.C.o.E.a.R.-T., Quantitative ReverseTranscription-Polymerase Chain Reaction to Study mRNA Decay: Comparison of Endpoint and Real-Time Methods. Analytical Biochemistry, 2000. 285: p. 194-204.
85. Ross, R., Atherosclerosis-an in?ammatory disease. N. Engl. J. Med, 1999. 340: p. 115-126.
86. Lindner V, F.J., Reidy MA, , Mouse model of arterial injury. Circ Res 1993. 73: p. 792-796.
87. Li J, H.S., Guo ZG., Platelet-derived growth factor stimulated vascular muscle cell proliferation and its molecular mechanism. Acta Pharmacol Sin, 2000. 21(4): p. 340-344.
88. Jr, B.A., The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol., 1996. 14: p. 649-683.
89. Y, K.M.B.-N., Phosphorylation meets ubiquitination:the control of NF-kB activity. Ann Rev Immunol, 2000. 18: p. 621-663.
90. Schett G, X.Q., Amberger A, Van der Zee R, Recheis H, Willeit J, Wick G, Autoantibodies against Heat Shock Protein 60 Mediate Endothelial Cytotoxicity. J. Clin. Invest., 1995. 96: p. 2569-2577.
91. Cybulsky, M.I., and Gimbrone, M.A., Jr. , Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. . Science, 1991. 251: p. 788-791.
92. Johnson RC, C.S., Dong ZM, Ordovas JM, Mayadas TN, Herz J, Hynes RO, Schaefer EJ, Wagner DD., Absence of P-selectin delays fatty streak formation in mice. J. Clin. Invest, 1997. 99(5): p. 1037-1043.
93. Dong, Z.M., et al. , The combined role of P- and E-selectins in atherosclerosis. J. Clin. Invest, 1998. 102: p. 145-152.
94. Collins, R.G., et al., P-selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J. Exp. Med, 2000. 191: p. 189-194.
95. Dong, Z.M., Brown, A.A., and Wagner, D.D. , Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice. Circulation, 2000. 101: p. 2290-2295.
96. Boisvert, W.A., Santiago, R., Curtiss, L.K., and Terkeltaub, R.A., A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor deficient mice. J. Clin. Invest, 1998. 101(2): p. 353-363.
97. Boring, L., Gosling, J., Cleary, M., and Charo, I.F. , Decreased lesion formation in CCR2 -/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature, 1998. 394: p. 894-897.
98. Gu L, O.Y., Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ., Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol. Cell. , 1998. 2(2): p. 275-281.
99. JR., H., The role of MCP-1 in atherosclerosis. Stem Cells, 2000. 18(1): p. 65-6.
100. D, S., Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem 1997. 272: p. 20963-6.
101. Keaney JF Jr, G.Y., Cunningham D, et al. , Vascular incorporation of alpha-tocopherol prevents endothelial dysfunction due to oxidized LDL by inhibiting protein kinase Cstimulation. J Clin Invest, 1996. 98(2): p. 386-394.
102. Mehta A, Y.B., Khan S, et al, Oxidized low-density lipoproteins facilitate leukocyte adhesion to aortic intima without affecting endothelium-dependent relaxation: role of P-selectin. Arterioscler Thromb Vasc Biol, 1995. 15: p. 2076-2083.
103. Kleindienst R, X.Q., Willeit J, Waldenberger FR, Weimann S, Wick G., Immunology of atherosclerosis. Demonstration of heat shock protein 60 expression and T lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions. . Am J Pathol, 1993. 142(6): p. 1927-1937.
104. Han Z, T.Q., Park S, et al., Two Hsp70 family members expressed in atherosclerotic lesions. Proc Natl Acad Sci U S A, 2003. 100(3): p. 1256-1261.
105. Wick G, R.M., Amberger A, Metzler B, Mayr M, Falkensammer G, Xu Q., Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue. Faseb J, 1997. 11(13): p. 1199-1207.
106. Zhu W, R.P., Pellegatta F, Catapano AL., Oxidized-LDL induce the expression of heat shock protein 70 in human endothelial cells. Biochem. Biophys. Res. Commun., 1994. 200(1): p. 389-394.
107. Shin, B.K., Wang, H., Yim, A. M., Le, N. F., Brichory, F., Jang, J. H., Zhao, R., Puravs, E., Tra, J., Michael, C. W., Misek, D. E., Hanash, S. M., Global profiling of the cell surface proteome of cancer cells uncovers an abundance of proteins with chaperone function. J. Biol. Chem, 2003. 278: p. 7607-7616.
108. Virginia L. Vega, M.R.-S., Tiffany Frey, , Hsp70 Translocates into the Plasma Membrane after Stress and Is Released into the Extracellular Environment in a Membrane-Associated Form that Activates Macrophages. TheJournal of Immunology, 2008. 180(6): p. 4299-4307.
109. Botzler, C., Ellwart, J., Gunther, W., Eissner, G., Multhoff, G, Synergistic effects of heat and ET-18-OCH3 on membrane expression of hsp70 and lysis of leukemic K562 cells. Exp. Hematol, 1999. 27(3): p. 470-478.
110. Gehrmann M, P.K., Hutzler P, Gastpar R, Margulis B, Multhoff G., Effects of antineoplastic agents on cytoplasmic and membrane- bound heat shock protein 70 (Hsp70) levels. Biol. Chem, 2002. 383(11): p. 1715-1725.
111. Gehrmann, M., Brunner, M., Pfister, K., Reichle, A., Kremmer, E., Multhoff, G. , Differential up-regulation of cytosolic and membranebound heat shock protein 70 in tumor cells by anti-inflammatory drugs. Clin. Cancer Res, 2004. 10(10): p. 3354-3363.
112. Arispe, N., M. Doh, and A. De Maio. , Lipid interaction differentiates the constitutve and stress-induced heat shock proteins Hsc70 and Hsp70. Cell Stress Chaperones 2002. 7(4): p. 330-338.
113. Zhan R, L.X., Liu X, Wang X, Gong J, Yan L, Wang L, Wang Y, Wang X, Qian LJ., Heat shock protein 70 is secreted from endothelial cells by a non-classical pathway involving exosomes. Biochem Biophys Res Commun, 2009. 387(2): p. 229-33.
114. Dybdahl B, S.S., Waage A, et al. , Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart, 2005. 91(3): p. 299-304.
115. Mamoru S, Y.S., Tomonari A, et al. , Elevated circulating levels of heat shock protein 70 are related to systemic inflammatory reaction through monocyte Toll signal in patientswith heart failure after acute myocardial infarction. Europ J Heart Failure, 2006. 8: p. 810-815.
116. Seifert PS, M.M., Roth I, Bhakdi S., Analysis of complement C3 activation products in human atherosclerotic lesions. Atherosclerosis, 1991. 91(1-2): p. 155-62.
117. Pang AS, K.A., Minta JO., C3 deposition in cholesterol-induced atherosclerosis in rabbits: a possible etiologic role for complement in atherogenesis. J Immunol., 1979. 123(3): p. 1117-22.
118. Buono C, C.C., Witztum JL, Maguire GF, Connelly PW, Carroll M, Lichtman AH., Influence of C3 deficiency on atherosclerosis. Circulation, 2002. 105(25): p. 3025-31.
119. Ravetch JV, K.J.-P., Fc Receptors. Annu Rev Immunol 1991. 9: p. 457-92.
120. Unkeless JC, S.Z., Lin C, DeBeus E., Function of human Fc gamma RIIA and Fc gamma RIIIB. Semin Immunol 1995. 7(1): p. 37-44.
121. Wang, Y., C. G. Kelly, J. T. Kartunen, T. Whittall, P. J. Lehner, L. Duncan, P. MacAry, J. S. Younson, M. Singh, W. Oehlmann, et al. , CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC chemokines. Immunity, 2001. 15(971-983).
122. Wang, Y., C. G. Kelly, M. Singh, E. G. McGowan, A.-S. Carrara, L. A. Bergmeier, and T. Lehner. , Stimulation of Th1-polarizing cytokines, C-C chemokines, maturation of dendritic cells and adjuvant function by the peptide binding fragment of heat shock protein 70. . J. Immunol. , 2002. 169: p. 2422-2429.
123. Whittall, T., Y. Wang, J. Younson, C. Kelly, L. Bergmeier, B. Peters, M. Singh, and T. Lehner. , Interaction between the CCR5 chemokine receptors and microbial HSP70. . J. Immunol. , 2006. 36: p. 2304-2314.
124. Ahn, H.Y., Hadizadeh, K. R., Seul, C., Yun, Y. P., Vetter, H., and Sachinidis, A, Epigallocathechin-3 gallate selectively inhibits the PDGF-BB-induced intracellular signaling transduction pathway in vascular smooth muscle cells and inhibits transformation of sis-transfected NIH 3T3 fibroblasts and human glioblastoma cells (A172). . Mol. Biol. Cell., 1999. 10(4): p. 1093-1104.
125. Akishita, M., Ito, M., Lehtonen, J. Y., Daviet, L., Dzau, V. J., and Horiuchi, M., Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and in?uences fetal vascular growth. J. Clin. Invest. , 1999. 103: p. 63-71.
126. Ledebur HC, P.T., Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells. Essential roles of a variant NF-kappa B site and p65 homodimers. J. Biol. Chem., 1995. 270(2): p. 933-943.
127. Wrighton, C.J., Hofer-Warbinek, R., Moll, T., Eytner, R., Bach, F. H., and de Martin, R., xxxxxx. J. Exp. Med. , 1996 183: p. 1013-1022.
128. Boyle, E.M., Jr., Kovacich, J. C., Canty, T. G., Jr., Morgan, E. N., Chi, E.,Verrier, E. D., and Pohlman, T. H., Inhibition of nuclear factor-kappa B nuclear localization reduces human E-selectin expression and the systemic inflammatory response. Circulation 1998. 98: p. 282-288.
129. Mulvany, M.J., and Aalkjaer, C., Structure and function of small arteries. . Physiol. Rev., 1990. 70: p. 921-961.
130. Nimmerjahn F, R.J., Fcgamma receptors: old friends and new family members. Immunity, 2006. 24(1): p. 19-28.
131. Hazenbos WL, H.I., Meyer D, Hofhuis FM, Renardel de Lavalette CR, Schmidt RE, Capel PJ, van de Winkel JG, Gessner JE, van den Berg TK, Verbeek JS., Murine IgG1 complexes trigger immune effector functions predominantly via Fc gamma RIII (CD16). Immunol. , 1998. 161(6): p. 3026-32.
132. Auwardt RB, M.S., Chen CG, Power DA., Regulation of nuclear factor kappaB by corticosteroids in rat mesangial cells. J Am Soc Nephrol, 1998. 9(9): p. 1620-1628.
133. Martin-Ventura JL, B.-C.L., Munoz-Garcia B, Gomez Hernandez A, Arribas A, Ortega L, Tunon J, Egido J. , NF-kappaB activation and Fas ligand overexpression in blood and plaques of patients with carotid atherosclerosis: potential implication in plaque instability. Stroke, 2004. 35(2): p. 458-463.
134. Hernandez-Presa M, B.C., Ortego M, Tunon J, Renedo G, Ruiz Ortega M, Egido J., Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation, 1997. 95(6): p. 1532-1541.
135. Monaco C, A.E., Kiriakidis S, Mauri C, Bicknell C, Foxwell B, Cheshire N, Paleolog E, Feldmann M, Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis. Proc Natl Acad Sci USA, 2004. 101(15): p. 5634-5639.
136. Brand K, P.S., Rogler G, Bartsch A, Brandl R, Knuechel R, Page M, Kaltschmidt C, Baeuerle PA, Neumeier D., Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest, 1996. 97(7): p. 1715-1722.
137. Masuda M, T.H., Increase of soluble Fc gamma RIIIa derived from macrophages in plasma from patients with atherosclerosis. Rinsho Byori, 2002. 50(5): p. 502-505.
138. Daeron, M., Fc receptor biology. Annu. Rev. Immunol., 1997. 15: p. 203-234.
139. Gessner, J.E., H. Heiken, A. Tamm, and R. E. Schmidt. , The IgG Fc receptor family. . Ann. Hematol., 1998. 76 p. 231-248.
140. Ravetch, J.V., Fc receptors. Curr. Opin. Immunol. , 1997. 9: p. 121-125.
141. Majid Ghayour-Mobarhan, David J. Lamb, Shima Tavallaie, Gordon A. A. Ferns. Relationship between plasma cholesterol, von Willebrand factor concentrations, extent of atherosclerosis and antibody titres to heat shock proteins-60, -65 and -70 in cholesterol-fed rabbits. Int. J. Exp. Path..2007.8: 249-255.
1. R., R., The pathogenesis of atherosclerosis: a perspective for the 1990s. . Nature 1993. 362(6423): p. 801-9.
2. R., R., Atherosclerosis—an inflammatory disease. . N EnglJ Med 1999. 340(2): p. 115-26.
3. Libby P, R.P., Maseri A., Inflammation and atherosclerosis. . Circulation 2002. 105(9): p. 1135-43.
4. GK., H., Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001. 21(12): p. 1876-90.
5. Wick G, X.Q.A.a.a.d.-. and e.E.G.–66., Atherosclerosis—an autoimmune disease. . Exp Gerontol, 1999. 34(4): p. 559-66.
6. Xu QB, e.a., Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks, and atherosclerotic plaques in young and aged human specimens. . Clin Immunol Immunopathol 1990. 56(3): p. 344-59.
7. RI., M., Cells in stress: transcriptional activation of heat shock genes. Science 1993. 259(5100): p. 1409-10.
8. Patterson C, C.D., Welcome to the machine: a cardiologist’s introduction toprotein folding and degradation. Circulation 2002. 106(21).
9. Xu Q, W.G., The role of heat shock proteins in protection and pathophysiology of the arterial wall. . Mol Med Today 1996. 2(9): p. 372-9.
10. Benjamin IJ, M.D., Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease. Circ Res 1998. 83(2): p. 117-32.
11. AG., P., Heat shock proteins, inflammation, and cardiovascular disease. 105, 2002. 8(1012-7).
12. Wick G, P.H., Millonig G. , Atherosclerosis as an autoimmune disease: an update. . Trends Immunol, 2001. 22(12): p. 665-9.
13. Q., X., Arterioscler Thromb Vasc Biol Arterioscler Thromb Vasc Biol 2002. 22: p. 1547-59.
14. J.L. Brodsky, Post-translational translocation: not all Hsc70s are created equal. Trends Biochem. , 1996. 21: p. 122-126.
15. Zhu Jianhui , e.a., Association of Serum Antibodies to Heat-Shock Protein 65 With Coronary Calcification Levels: Suggestion of Pathogen-Triggered Autoimmunity in Early Atherosclerosis. Circulation, 2004. 109: p. 36-41.
16. Asea A, K.S., Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, et al. , HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. . Nat Med 2000. 6(4): p. 435-42.
17. Pockley AG, G.A., Thulin T, et al, Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension Hypertension, 2003. 42(3): p. 235-8.
18. Jacob George, S.G., Iris Barshack, Madhavir Singh, Sara Pri-Chen, Shlomo Laniado, Gad Keren, , Accelerated Intimal Thickening in Carotid Arteries of Balloon-Injured Rats After Immunization Against Heat Shock Protein 70. JACC, 2001. 38(5): p. 1564-9.
19. Young RA, E.T., Stress proteins, infection, and immune surveillance. Cell, 1989. 59(1): p. 5-8.
[1]邓红艳,廖丽娅,张雨,等. 2型糖尿病患者亚临床动脉粥样硬化与胰岛素抵抗[J].临床心血管病杂志,2007,23(4):265-266.
[2] Frosteg?rd Alan G. Pockley, Anastasia Georgiades A, et al.Serum Heat Shock Protein 70 Levels Predict the Development of Atherosclerosis in Subjects With Established Hypertension. Hypertension 2003,42:235-238.
[3]魏蒙,顾水明,张昀昀,等.普伐他汀福辛普利及合用对大鼠心肌梗死后肿瘤坏死因子-表达及心室重构的影响[J].中华心血管病杂志,2005,33(5):444-447.
[4]邹继红,史兆荣.老年2型糖尿病脂联素和C反应蛋白与动脉粥样硬化的关系[J].中华老年心脑血管病杂志, 2007 ,9(9):599-601.
[5] Ghayour-Mobarhan M,Lamb D J, Tavallaie S,et al. Relationship between plasma cholesterol, von Willebrand factor concentrations, extent of atherosclerosis and antibody titres to heat shock proteins-60, -65 and -70 in cholesterol-fed rabbits[J]. Int J Exp Path, 2007, 88(4):249–255.
[6] Wu T Ch,Ma J X, Chen Sh,et al. Association of plasma antibodies against the inducible Hsp70 with hypertension and harsh working conditions[J]. Cell Stress Chaperones,2001,6(4):394-401.
[7] Kim Y K, Suarez J,Hu Y,et al. Deletion of the Inducible 70-kDa Heat Shock Protein Genes in Mice Impairs Cardiac Contractile Function and Calcium Handling Associated With Hypertrophy[J]. Circulation,2006,113(5):2589-2597.
[8] Gross C,Hansch D,Gastpar R,et al . Interaction of Heat Shock Protein 70 Peptide with NK Cells Involves the NK Receptor CD94[J]. Biological chemistry ,2003,384(12):267– 279.
[9] Xu Q B. Role of Heat Shock Proteins in Atherosclerosis[R]. Arterioscler Thromb Vasc Biol.1547-1559.