Xu Ruixia, Chen Jinghai, Cong Xiangfeng, Hu Shengshou, Chen Xi
Research Center for Cardiovascular Regenerative Medicine, Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 167 Beilishilu, Beijing 100037, People's Republic of China.
J Cell Biochem. 2008 Jan 1;103(1):256-69. doi: 10.1002/jcb.21402.
Cell therapy with bone marrow-derived mesenchymal stem cells (MSCs) has been shown to have great promises in cardiac repair after myocardial infarction. However, poor viability of transplanted MSCs in the infracted heart has limited the therapeutic efficacy. Our previous studies have shown in vitro that rat MSCs undergo caspase-dependent apoptosis in response to hypoxia and serum deprivation (Hypoxia/SD). Recent findings have implicated statins, an established class of cholesterol-lowering drugs, enhance the survival of cells under various conditions. In this study, we investigated the effect of lovastatin on rat MSCs apoptosis induced by Hypoxia/SD, focusing in particular on regulation of mitochondrial apoptotic pathway and the survival signaling pathways. We demonstrated that lovastatin (0.01-1 microM) remarkably prevented MSCs from Hypoxia/SD-induced apoptosis through inhibition of the mitochondrial apoptotic pathway, leading to attenuation of caspase-3 activation. The loss of mitochondrial membrane potential and cytochrome-c release from mitochondria to cytosol were significantly inhibited by lovastatin. Furthermore, the antiapoptotic effect of lovastatin on mitochondrial apoptotic pathway was effectively abrogated by both PI3K inhibitor, LY294002 and ERK1/2 inhibitor, U0126. The phosphorylations of Akt/GSK3 beta and ERK1/2 stimulated by lovastatin were detected. The activation of ERK1/2 was inhibited by a PI3K inhibitor, LY294002, but U0126, a ERK1/2 inhibitor did not inhibit phosphorylation of Akt and GSK3 beta. These data demonstrate that lovastatin protects MSCs from Hypoxia/SD-induced apoptosis via PI3K/Akt and MEK/ERK1/2 pathways, suggesting that it may prove a useful therapeutic adjunct for transplanting MSCs into damaged heart after myocardial infarction.
骨髓间充质干细胞（MSCs）的细胞疗法已被证明在心肌梗死后的心脏修复中具有巨大潜力。然而，移植的MSCs在梗死心脏中的低存活率限制了治疗效果。我们之前的研究表明，在体外，大鼠MSCs在缺氧和血清剥夺（Hypoxia/SD）条件下会经历半胱天冬酶依赖性凋亡。最近的研究发现，他汀类药物（一类已确定的降胆固醇药物）可在各种条件下提高细胞存活率。在本研究中，我们研究了洛伐他汀对Hypoxia/SD诱导的大鼠MSCs凋亡的影响，特别关注线粒体凋亡途径和生存信号通路的调节。我们证明，洛伐他汀（0.01 - 1 microM）通过抑制线粒体凋亡途径显著阻止了MSCs因Hypoxia/SD诱导的凋亡，导致半胱天冬酶-3激活减弱。洛伐他汀显著抑制了线粒体膜电位的丧失以及细胞色素c从线粒体释放到细胞质中。此外，PI3K抑制剂LY294002和ERK1/2抑制剂U0126均有效消除了洛伐他汀对线粒体凋亡途径的抗凋亡作用。检测到洛伐他汀刺激的Akt/GSK3β和ERK1/2的磷酸化。ERK1/2的激活被PI3K抑制剂LY294002抑制，但ERK1/2抑制剂U0126并未抑制Akt和GSK3β的磷酸化。这些数据表明，洛伐他汀通过PI3K/Akt和MEK/ERK1/2途径保护MSCs免受Hypoxia/SD诱导的凋亡，这表明它可能被证明是心肌梗死后将MSCs移植到受损心脏中的一种有用的治疗辅助手段。
