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Lovastatin protects mesenchymal stem cells against hypoxia‐ and serum deprivation‐induced apoptosis by activation of PI3K/Akt and ERK1/2
Author(s) -
Xu Ruixia,
Chen Jinghai,
Cong Xiangfeng,
Hu Shengshou,
Chen Xi
Publication year - 2007
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21402
Subject(s) - lovastatin , pi3k/akt/mtor pathway , protein kinase b , apoptosis , ly294002 , microbiology and biotechnology , mesenchymal stem cell , hypoxia (environmental) , pharmacology , biology , cancer research , chemistry , signal transduction , endocrinology , biochemistry , cholesterol , organic chemistry , oxygen
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.