Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, PR China.
Int J Mol Med. 2011 Sep;28(3):397-403. doi: 10.3892/ijmm.2011.682. Epub 2011 Apr 20.
The present study evaluated potential mechanisms of hydrogen sulfide (H2S)-mediated cardioprotection using an in vitro chemical hypoxia-induced injury model. We have demonstrated that H2S protects H9c2 cardiomyoblasts (H9c2) against chemical hypoxia-induced injuries by suppressing oxidative stress and preserving mitochondrial function. The aim of this study was to investigate the role of heat shock protein 90 (HSP90) in cardioprotection of H2S in H9c2 cells. The findings of the present study showed that cobalt chloride (CoCl2), a chemical hypoxia agent, significantly enhanced the expression of HSP90 and that 17-allylamino-17-demethoxy geldanamycin (17-AAG), a selective inhibitor of HSP90, aggravated concentration-dependent cytotoxicity induced by CoCl2. Exogenous administration of NaHS (a donor of H2S) augmented not only HSP90 expression under normal conditions, but also CoCl2-induced overexpression of HSP90. Pre-treatment with 17-AAG significantly blocked the cardioprotection of H2S against CoCl2-induced injuries, leading to increases in cytotoxicity and apoptotic cells. Furthermore, pre-treatment with 17-AAG also antagonized the inhibitory effects of NaHS on overproduction of reactive oxygen species (ROS), a loss of mitochondrial membrane potential (MMP) and ATP depletion induced by CoCl2. In conclusion, these results demonstrate that the increased expression of HSP90 may be one of the endogenous defensive mechanisms for resisting chemical hypoxia-induced injury in H9c2 cells. We also provide novel evidence that HSP90 mediates the cardioprotection of H2S against CoCl2-induced injuries by its antioxidant effect and preservation of mitochondrial function in H9c2 cells.
本研究采用体外化学缺氧诱导损伤模型评估了硫化氢（H2S）介导的心脏保护的潜在机制。我们已经证明，H2S 通过抑制氧化应激和维持线粒体功能来保护 H9c2 心肌细胞（H9c2）免受化学缺氧诱导的损伤。本研究旨在探讨热休克蛋白 90（HSP90）在 H2S 对 H9c2 细胞心脏保护中的作用。本研究的结果表明，氯化钴（CoCl2），一种化学缺氧剂，显著增强 HSP90 的表达，而 17-烯丙基-17-去甲氧基格尔德霉素（17-AAG），HSP90 的选择性抑制剂，加剧了 CoCl2 诱导的浓度依赖性细胞毒性。外源性给予 NaHS（H2S 的供体）不仅增强了正常条件下 HSP90 的表达，而且增强了 CoCl2 诱导的 HSP90 过表达。17-AAG 预处理显著阻断了 H2S 对 CoCl2 诱导损伤的心脏保护作用，导致细胞毒性和凋亡细胞增加。此外，17-AAG 的预处理还拮抗了 NaHS 对 CoCl2 诱导的活性氧（ROS）过度产生、线粒体膜电位（MMP）丧失和 ATP 耗竭的抑制作用。总之，这些结果表明 HSP90 的表达增加可能是 H9c2 细胞抵抗化学缺氧诱导损伤的内源性防御机制之一。我们还提供了新的证据表明，HSP90 通过其抗氧化作用和维持线粒体功能来介导 H2S 对 CoCl2 诱导损伤的心脏保护作用。
