Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
Clin Sci (Lond). 2012 Jan;122(1):33-42. doi: 10.1042/CS20110114.
Leptin contributes to the pathogenesis of atherosclerosis. Ang II (angiotensin II), a proatherogenic cytokine, increases leptin synthesis in cultured adipocytes. Statin suppresses leptin expression in adipocytes and human coronary artery endothelial cells. However, the effect of Ang II and statin on leptin expression in VSMCs (vascular smooth muscle cells), the major cell types in atheroma, is poorly understood. Thus the aim of the present study was to investigate the molecular mechanism of atorvastatin for reducing leptin expression after Ang II stimulation in VSMCs. VSMCs from human coronary artery were cultured. Ang II stimulation increased leptin protein and mRNA and phospho-JNK (c-Jun N-terminal kinase) expression. Exogenous addition of Dp44mT (2,2'-dipyridyl-N,N-dimethylsemicarbazone) and mevalonate increased leptin protein expression similarly to Ang II. Atorvastatin, SP600125, JNK siRNA (small interfering RNA) and NAC (N-acetylcysteine) completely attenuated the leptin and phospho-JNK protein expression induced by Ang II. Ang II significantly increased ROS (reactive oxygen species) formation in human VSMCs. Addition of atorvastatin and NAC significantly attenuated the formation of ROS induced by Ang II. Addition of atorvastatin and SP600125 inhibited the phosphorylation of Rac1 induced by Ang II. The gel shift and promoter activity assay showed that Ang II increased AP-1 (activator protein-1)-binding activity and leptin promoter activity, while SP600125, NAC and atorvastatin inhibited the AP-1-binding activity and leptin promoter activity induced by Ang II. Ang II significantly increased the migration and proliferation of cultured VSMCs, while addition of atorvastatin, SP600125, NAC and leptin siRNA before Ang II stimulation significantly inhibited the migration and proliferation of VSMCs induced by Ang II. Ang II significantly increased secretion of leptin from human VSMCs, and addition of SP600125, atorvastatin and NAC before Ang II stimulation almost completely inhibited the leptin secretion induced by Ang II. In conclusion, Ang II induces leptin expression in human VSMCs, and atorvastatin could inhibit the leptin expression induced by Ang II. The inhibitory effect of atorvastatin on Ang II-induced leptin expression was mediated by Rac, ROS and JNK pathways.
瘦素参与动脉粥样硬化的发病机制。血管紧张素 II（血管紧张素 II）是一种促动脉粥样硬化细胞因子，可增加培养脂肪细胞中的瘦素合成。他汀类药物可抑制脂肪细胞和人冠状动脉内皮细胞中的瘦素表达。然而，血管紧张素 II 和他汀类药物对动脉粥样硬化中主要细胞类型——血管平滑肌细胞（VSMCs）中瘦素表达的影响知之甚少。因此，本研究旨在探讨阿托伐他汀在血管紧张素 II 刺激后降低 VSMCs 中瘦素表达的分子机制。从人冠状动脉培养 VSMCs。血管紧张素 II 刺激增加了瘦素蛋白和 mRNA 以及磷酸化 JNK（c-Jun N-末端激酶）的表达。外源性添加 Dp44mT（2,2'-二吡啶-N，N-二甲脒）和甲羟戊酸同样增加了瘦素蛋白的表达，类似于血管紧张素 II。阿托伐他汀、SP600125、JNK siRNA（小干扰 RNA）和 NAC（N-乙酰半胱氨酸）完全减弱了血管紧张素 II 诱导的瘦素和磷酸化 JNK 蛋白的表达。血管紧张素 II 显著增加了人 VSMCs 中活性氧（ROS）的形成。添加阿托伐他汀和 NAC 可显著减弱血管紧张素 II 诱导的 ROS 形成。添加阿托伐他汀和 SP600125 抑制了血管紧张素 II 诱导的 Rac1 磷酸化。凝胶迁移和启动子活性测定表明，血管紧张素 II 增加了 AP-1（激活蛋白-1）结合活性和瘦素启动子活性，而 SP600125、NAC 和阿托伐他汀抑制了血管紧张素 II 诱导的 AP-1 结合活性和瘦素启动子活性。血管紧张素 II 显著增加了培养的 VSMCs 的迁移和增殖，而在血管紧张素 II 刺激前添加阿托伐他汀、SP600125、NAC 和瘦素 siRNA 可显著抑制血管紧张素 II 诱导的 VSMCs 的迁移和增殖。血管紧张素 II 显著增加了人 VSMCs 中瘦素的分泌，而在血管紧张素 II 刺激前添加 SP600125、阿托伐他汀和 NAC 几乎完全抑制了血管紧张素 II 诱导的瘦素分泌。总之，血管紧张素 II 诱导人 VSMCs 中瘦素的表达，阿托伐他汀可抑制血管紧张素 II 诱导的瘦素表达。阿托伐他汀对血管紧张素 II 诱导的瘦素表达的抑制作用是通过 Rac、ROS 和 JNK 途径介导的。
