Biological significance of decreased HSP27 in human atherosclerosis
Biological significance of decreased HSP27 in human atherosclerosis
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DOI：
10.1161/01.atv.0000220108.97208.67
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发表时间：
2006-06-01
影响因子：
8.7
通讯作者：
Meilhac, Olivier
中科院分区：
文献类型：
--
作者：
Martin-Ventura, Jose Luis;Nicolas, Valentin;Meilhac, Olivier
目的 - 由于罪魁祸首动脉粥样硬化斑块含有蛋白酶，我们推测动脉粥样硬化斑块释放的热休克蛋白 27 (HSP27) 减少可能是由于蛋白水解作用。我们评估了 HSP27 在蛋白水解损伤下人血管平滑肌细胞 (VSMC) 中的作用。方法和结果 - 罪魁祸首动脉粥样硬化斑块中存在活性纤溶酶。重组 HSP27 被纤溶酶裂解，并且这种作用可以被不同的抑制剂阻止。将乳腺对照动脉内膜与纤溶酶一起孵育后，出现 HSP27 的片段和聚集形式。动脉粥样硬化斑块与重组 HSP27 或乳腺内动脉共孵育会导致 HSP27 蛋白水解。 VSMCs与纤溶酶一起孵育后，HSP27被过度表达、磷酸化、聚集，并从细胞骨架重新分布到细胞质、细胞核和细胞膜。在 HSP27 siRNA 处理的 VSMC 中，纤溶酶诱导的 VSMC 凋亡显着较高。动脉粥样硬化斑块的免疫组织化学分析表明，纤溶酶（原）和凋亡细胞位于核心/肩部，而 HSP27 和 VSMC 主要在帽/中层表达。结论 - 细胞外 HSP27 可以被动脉粥样硬化斑块释放的酶降解，可能反映了蛋白水解失衡。细胞内 HSP27 下调可降低 VSMC 对蛋白水解诱导的细胞凋亡的抵抗力。 HSP27 可能在预防斑块不稳定和破裂方面发挥关键作用。
Objective - Because culprit atherosclerotic plaques contain proteases, we hypothesized that the diminished heat shock protein 27 (HSP27) released by atherosclerotic plaques could be due to proteolysis. We assessed the role of HSP27 in human vascular smooth muscle cells (VSMCs) under proteolytic injury.Methods and Results - Active plasmin is present in culprit atherosclerotic plaques. Recombinant HSP27 was cleaved by plasmin and this effect was prevented by different inhibitors. Fragments and aggregated forms of HSP27 appeared after incubation of mammary control endarteries with plasmin. Coincubation of atherosclerotic plaques with recombinant HSP27 or mammary endarteries led to HSP27 proteolysis. After incubation of VSMCs with plasmin, HSP27 was overexpressed, phosphorylated, aggregated, and redistributed from the cytoskeleton to the cytosol, nucleus, and cell membrane. Plasmin-induced VSMC apoptosis was significantly higher in VSMCs treated by HSP27 siRNA. Immunohistochemical analysis of atherosclerotic plaques showed that plasmin(ogen) and apoptotic cells are localized in the core/shoulder whereas HSP27 and VSMCs are mainly expressed in the cap/media.Conclusions - Extracellular HSP27 can be degraded by enzymes released from atherosclerotic plaques and may reflect a proteolytic imbalance. Intracellular HSP27 downregulation decreases VSMCs resistance to proteolytically-induced apoptosis. HSP27 might play a pivotal role in the prevention of plaque instability and rupture.