Division of Life Sciences, Korea University, Seoul 136-701, South Korea.
Department of Medicine, Graduate School, University of Ulsan, Seoul 138-736, South Korea.
J Mol Cell Cardiol. 2014 Jul;72:157-67. doi: 10.1016/j.yjmcc.2014.03.008. Epub 2014 Mar 18.
The molecular chaperone heat shock protein 90 (HSP90) is overexpressed in plaques of atherosclerosis patients, and is associated with plaque instability. However, the role of HSP90 in atherosclerosis remains unclear. The present study investigated the effects of HSP90 inhibition on migration and proliferation of vascular smooth muscle cells (VSMCs) and involvement in atherosclerosis. To examine the role of HSP90 in VSMC migration, VSMCs were treated with the specific HSP90 inhibitors, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) and STA-9090. Results of a chemotaxis assay showed that the HSP90 inhibitors suppress migration of VSMCs. HSP90 inhibition also prevented invasion and sprout formation of VSMCs via inhibition of matrix metalloproteinase-2 proteolytic activity. Results of a flow cytometric analysis showed that HSP90 inhibition induces cell cycle arrest via regulation of cyclin D3, PCNA and pRb. To investigate the role of HSP90 in the development of atherosclerosis, low-density lipoprotein receptor (LDLR) deficient mice were fed with a high cholesterol diet for 4weeks and treated with 17-AAG for 8weeks. HSP90 inhibition suppressed migration of VSMCs into atherosclerotic plaque lesions in high cholesterol diet-stimulated LDLR(-/-) mice. Inhibition of HSP90 attenuates formation of atherosclerotic plaques via suppression of VSMC migration and proliferation, indicating that HSP90 inhibitors can be used as therapeutic agents for atherosclerosis and in stent restenosis.
热休克蛋白 90（HSP90）是一种分子伴侣，在动脉粥样硬化患者的斑块中过度表达，与斑块不稳定有关。然而，HSP90 在动脉粥样硬化中的作用尚不清楚。本研究探讨了 HSP90 抑制对血管平滑肌细胞（VSMCs）迁移和增殖的影响及其在动脉粥样硬化中的作用。为了研究 HSP90 在 VSMC 迁移中的作用，用特异性 HSP90 抑制剂 17-N-烯丙基-17-去甲氧基格尔德霉素（17-AAG）和 STA-9090 处理 VSMCs。趋化实验结果表明，HSP90 抑制剂抑制 VSMC 的迁移。HSP90 抑制还通过抑制基质金属蛋白酶-2 的蛋白水解活性来防止 VSMC 的侵袭和芽生形成。流式细胞术分析结果表明，HSP90 抑制通过调节周期蛋白 D3、PCNA 和 pRb 诱导细胞周期停滞。为了研究 HSP90 在动脉粥样硬化发展中的作用，用高胆固醇饮食喂养 LDLR 缺陷小鼠 4 周，并给予 17-AAG 治疗 8 周。HSP90 抑制抑制了高胆固醇饮食刺激的 LDLR（-/-）小鼠动脉粥样硬化斑块病变中 VSMC 的迁移。HSP90 抑制通过抑制 VSMC 迁移和增殖来减轻动脉粥样硬化斑块的形成，表明 HSP90 抑制剂可作为动脉粥样硬化和支架内再狭窄的治疗药物。
