Lovastatin protects mesenchymal stem cells against hypoxia‐ and serum deprivation‐induced apoptosis by activation of PI3K/Akt and ERK1/2
Lovastatin protects mesenchymal stem cells against hypoxia‐ and serum deprivation‐induced apoptosis by activation of PI3K/Akt and ERK1/2
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DOI：
10.1002/jcb.21402
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发表时间：
2008
影响因子：
4
通讯作者：
Rui-xia Xu;Jinghai Chen;X. Cong;Shengshou Hu;X. Chen
中科院分区：
文献类型：
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作者：
Rui-xia Xu;Jinghai Chen;X. Cong;Shengshou Hu;X. Chen
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很大的前景。然而，移植的MSCs在梗死心脏中的存活率差限制了治疗效果。我们之前的研究表明，在体外，大鼠MSC经历caspase依赖性凋亡，以响应缺氧和血清剥夺（缺氧/SD）。最近的研究结果表明，他汀类药物，一种既定的降胆固醇药物，在各种条件下增强细胞的存活。本研究旨在探讨洛伐他汀对缺氧/SD诱导的大鼠骨髓间充质干细胞凋亡的影响，特别是对线粒体凋亡通路和生存信号通路的调控。我们证明，洛伐他汀（0.01-1 µM）通过抑制线粒体凋亡途径，导致caspase-3活化减弱，显著防止MSC缺氧/SD诱导的凋亡。洛伐他汀可显著抑制线粒体膜电位的丧失和细胞色素c从线粒体释放到细胞质中。此外，洛伐他汀对线粒体凋亡途径的抗凋亡作用被PI 3 K抑制剂LY 294002和ERK 1/2抑制剂U 0126有效地消除。检测洛伐他汀对Akt/GSK 3 β和ERK 1/2磷酸化的影响。ERK 1/2抑制剂LY 294002可抑制ERK 1/2的激活，而ERK 1/2抑制剂U 0126则不抑制Akt和GSK 3 β的磷酸化。这些数据表明，洛伐他汀通过PI 3 K/Akt和MEK/ERK 1/2途径保护MSC免受缺氧/SD诱导的凋亡，这表明它可能被证明是心肌梗死后将MSC移植到受损心脏中的有用治疗辅助剂。J.细胞。103：256-269，2008.© 2007 Wiley利斯公司
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 µM) 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/GSK3β 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 GSK3β. 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. J. Cell. Biochem. 103: 256–269, 2008. © 2007 Wiley‐Liss, Inc.