热休克蛋白 70 通过 JNK/Elk-1 通路下调 ABCA1 和 ABCG1 的表达，从而加速动脉粥样硬化。
Heat shock protein 70 accelerates atherosclerosis by downregulating the expression of ABCA1 and ABCG1 through the JNK/Elk-1 pathway.
机构信息
Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China.
Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China; Department of Endocrinology, The First Hospital of Changsha, Changsha, Hunan 410005, China.
出版信息
Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Aug;1863(8):806-822. doi: 10.1016/j.bbalip.2018.04.011. Epub 2018 Apr 17.
BACKGROUND AND AIMS
Recent studies have suggested that heat shock protein 70 (HSP70) may play critical roles in cardiovascular disease. However, the effects of HSP70 on the development of atherosclerosis in apoE mice remain largely unknown. This study was to investigate the role and potential mechanism of HSP70 in atherosclerosis.
METHODS
HSP70 was overexpressed in apoE mice and THP-1-derived macrophages with lentiviral vectors. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaque in apoE mice fed the Western type diet. Moreover, immunostaining was employed to detect the expression of relative proteins in aortic sinus. Reporter gene and chromatin immunoprecipitation were performed to analyze the effect of Elk-1 on the promoter activity of ABCA1 and ABCG1; [H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT).
RESULTS
Our results showed that HSP70 increased lipid accumulation in arteries and promoted the formation of atherosclerotic lesion. The capacity of cholesterol efflux was reduced in peritoneal macrophages isolated from HSP70-overexpressed apoE mice. The levels of ABCA1 and ABCG1 expression were also reduced in the peritoneal macrophages and the aorta from apoE mice in response to HSP70. The c-Jun N-terminal kinase (JNK) and ETS transcription factor (Elk-1) played a critical role in HSP70-induced downregulation ABCA1 and ABCG1. Further, HSP70 reduced RCT from macrophages to plasma, liver, and feces in apoE mice.
CONCLUSIONS
HSP70 promotes the progression of atherosclerosis in apoE mice by suppressing the expression of ABCA1 and ABCG1 through the JNK/Elk-1 pathway.
背景与目的
最近的研究表明，热休克蛋白 70（HSP70）可能在心血管疾病中发挥关键作用。然而，HSP70 对载脂蛋白 E （apoE）小鼠动脉粥样硬化发展的影响在很大程度上尚不清楚。本研究旨在探讨 HSP70 在动脉粥样硬化中的作用及其潜在机制。
方法
通过慢病毒载体在 apoE 小鼠和 THP-1 衍生的巨噬细胞中过表达 HSP70。用油红 O、苏木精-伊红和 Masson 染色法评估西方饮食喂养的 apoE 小鼠的动脉粥样硬化斑块。此外，采用免疫组化法检测主动脉窦中相对蛋白的表达。采用报告基因和染色质免疫沉淀法分析 Elk-1 对 ABCA1 和 ABCG1 启动子活性的影响；用[H]标记的胆固醇评估胆固醇流出和胆固醇逆向转运（RCT）的能力。
结果
我们的结果表明，HSP70 增加了动脉中的脂质堆积，促进了动脉粥样硬化病变的形成。与 HSP70 过表达的 apoE 小鼠来源的腹腔巨噬细胞相比，胆固醇流出能力降低。在 apoE 小鼠的腹腔巨噬细胞和主动脉中，HSP70 还降低了 ABCA1 和 ABCG1 的表达水平。c-Jun N-末端激酶（JNK）和 ETS 转录因子（Elk-1）在 HSP70 诱导的 ABCA1 和 ABCG1 下调中发挥关键作用。此外，HSP70 降低了 apoE 小鼠中从巨噬细胞到血浆、肝脏和粪便的 RCT。
结论
HSP70 通过 JNK/Elk-1 通路抑制 ABCA1 和 ABCG1 的表达，促进 apoE 小鼠动脉粥样硬化的进展。
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