Traditional & Complementary Medicine Program, RMIT Health Innovations Research Institute, School of Health Sciences, RMIT University, Bundoora, Victoria, Australia.
PLoS One. 2013;8(1):e51720. doi: 10.1371/journal.pone.0051720. Epub 2013 Jan 14.
Mitochondrial apoptosis pathway is an important target of cardioprotective signalling. Tanshinones, a group of major bioactive compounds isolated from Salvia miltiorrhiza, have been reported with actions against inflammation, oxidative stress, and myocardial ischemia reperfusion injury. However, the actions of these compounds on the chronic hypoxia-related mitochondrial apoptosis pathway have not been investigated. In this study, we examined the effects and molecular mechanisms of two major tanshonones, tanshinone IIA (TIIA) and cryptotanshinone (CT) on hypoxia induced apoptosis in H9c2 cells. Cultured H9c2 cells were treated with TIIA and CT (0.3 and 3 μΜ) 2 hr before and during an 8 hr hypoxic period. Chronic hypoxia caused a significant increase in hypoxia inducible factor 1α expression and the cell late apoptosis rate, which was accompanied with an increase in caspase 3 activity, cytochrome c release, mitochondria membrane potential and expression of pro-apoptosis proteins (Bax and Bak). TIIA and CT (0.3 and 3 μΜ), in concentrations without affecting the cell viability, significantly inhibited the late apoptosis and the changes of caspase 3 activity, cytochrome c release, and mitochondria membrane potential induced by chronic hypoxia. These compounds also suppressed the overexpression of Bax and reduced the ratio of Bax/Bcl-2. The results indicate that TIIA and CT protect against chronic hypoxia induced cell apoptosis by regulating the mitochondrial apoptosis signaling pathway, involving inhibitions of mitochondria hyperpolarization, cytochrome c release and caspase 3 activity, and balancing anti- and pro-apoptotic proteins in Bcl-2 family proteins.
线粒体凋亡途径是心脏保护信号的重要靶点。丹参酮是从丹参中分离得到的一组主要生物活性化合物，具有抗炎、抗氧化和心肌缺血再灌注损伤作用。然而，这些化合物对慢性缺氧相关的线粒体凋亡途径的作用尚未得到研究。在这项研究中，我们研究了两种主要丹参酮，丹参酮 IIA（TIIA）和隐丹参酮（CT）对 H9c2 细胞慢性缺氧诱导凋亡的作用及其分子机制。培养的 H9c2 细胞在 8 小时缺氧期前 2 小时和期间用 TIIA 和 CT（0.3 和 3 μM）处理。慢性缺氧导致缺氧诱导因子 1α表达和细胞晚期凋亡率显著增加，同时伴有 caspase 3 活性、细胞色素 c 释放、线粒体膜电位和促凋亡蛋白（Bax 和 Bak）表达增加。TIIA 和 CT（0.3 和 3 μM）在不影响细胞活力的浓度下，显著抑制慢性缺氧诱导的晚期凋亡和 caspase 3 活性、细胞色素 c 释放和线粒体膜电位的变化。这些化合物还抑制了 Bax 的过表达，并降低了 Bax/Bcl-2 的比值。结果表明，TIIA 和 CT 通过调节线粒体凋亡信号通路来保护细胞免受慢性缺氧诱导的细胞凋亡，涉及抑制线粒体超极化、细胞色素 c 释放和 caspase 3 活性，以及平衡 Bcl-2 家族蛋白中的抗凋亡和促凋亡蛋白。
