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在化学缺氧条件下,热休克蛋白 90 的表达增加可保护心肌细胞免受血清和葡萄糖剥夺引起的损伤。

Increased expression of heat shock protein 90 under chemical hypoxic conditions protects cardiomyocytes against injury induced by serum and glucose deprivation.

机构信息

Department of Cardiology, The Affiliated Hospital, Guangdong Medical College, Zhanjiang, PR China.

出版信息

Int J Mol Med. 2012 Nov;30(5):1138-44. doi: 10.3892/ijmm.2012.1099. Epub 2012 Aug 20.

Abstract

Heat shock proteins (HSPs) are critical for adaptation to hypoxia and/or ischemia. Previously, we demonstrated that cobalt chloride (CoCl2), a well-known hypoxia mimetic agent, is an inducer of HSP90. In the present study, we tested the hypothesis that CoCl₂-induced upregulation of HSP90 is able to provide cardioprotection in serum and glucose-deprived H9c2 cardiomyocytes (H9c2 cells). Cell viability was detected using a CCK-8 assay, while HSP90 expression was detected via western blotting. The findings of this study showed that serum and glucose deprivation (SGD) induced significant cytotoxicity, overproduction of reactive oxygen species (ROS) and a loss of mitochondrial membrane potential (MMP) in H9c2 cells. In addition, SGD downregulated the expression of HSP90 in a time-dependent manner. The selective inhibitor of HSP90 17-allylamino-17-demethoxygeldanamycin (17-AAG) aggravated SGD-induced cytotoxicity. CoCl₂ at 100 µM time-dependently enhanced the expression of HSP90. Treatment with CoCl₂ from 50 to 200 µM significantly attenuated cytotoxicity and the downregulation of HSP90 expression induced by SGD for 24 h, respectively. Notably, pretreatment of H9c2 cells with 17-AAG at 2 µM for 60 min before exposure to both CoCl2 (100 µM) and SGD significantly blocked the CoCl2-induced cardioprotective effect, demonstrated by decreased cell viability and MMP loss, as well as increased ROS generation. Taken together, these results suggest that HSP90 may be one of the endogenous defensive mechanisms for resisting ischemia-like injury in H9c2 cells, and that HSP90 plays an important role in chemical hypoxia-induced cardioprotection against SGD-induced injury by its antioxidation and preservation of mitochondrial function.

摘要

热休克蛋白(HSPs)对于适应缺氧和/或缺血至关重要。先前,我们证明了氯化钴(CoCl₂),一种众所周知的缺氧模拟剂,是 HSP90 的诱导剂。在本研究中,我们检验了以下假设:CoCl₂诱导的 HSP90 上调能够为血清和葡萄糖剥夺的 H9c2 心肌细胞(H9c2 细胞)提供心脏保护。使用 CCK-8 测定法检测细胞活力,通过 Western blot 检测 HSP90 表达。本研究的结果表明,血清和葡萄糖剥夺(SGD)诱导 H9c2 细胞产生显著的细胞毒性、活性氧(ROS)的过度产生以及线粒体膜电位(MMP)的丧失。此外,SGD 呈时间依赖性地下调 HSP90 的表达。HSP90 的选择性抑制剂 17- 丙烯酰胺-17-去甲氧基格尔德霉素(17-AAG)加重了 SGD 诱导的细胞毒性。100µM CoCl₂时间依赖性地增强了 HSP90 的表达。用 50 至 200µM CoCl₂处理分别显著减轻了 24 小时 SGD 诱导的细胞毒性和 HSP90 表达的下调。值得注意的是,在用 100µM CoCl₂和 SGD 处理之前,用 2µM 17-AAG 预处理 H9c2 细胞 60 分钟,显著阻断了 CoCl₂诱导的心脏保护作用,表现为细胞活力和 MMP 丧失降低,以及 ROS 生成增加。总之,这些结果表明 HSP90 可能是 H9c2 细胞抵抗类似缺血损伤的内源性防御机制之一,并且 HSP90 通过抗氧化和维持线粒体功能在化学缺氧诱导的对 SGD 诱导损伤的心脏保护中发挥重要作用。

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