Atorvastatin treatment improves the effects of mesenchymal stem cell transplantation on acute myocardial infarction: The role of the RhoA/ROCK/ERK pathway
Atorvastatin treatment improves the effects of mesenchymal stem cell transplantation on acute myocardial infarction: The role of the RhoA/ROCK/ERK pathway
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阿托伐他汀治疗改善间充质干细胞移植治疗急性心肌梗死的效果：RhoA/ROCK/ERK通路的作用
DOI：
10.1016/j.ijcard.2014.07.071
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发表时间：
2014-10-20
影响因子：
3.5
通讯作者：
Jin, Chen
中科院分区：
文献类型：
--
作者：
Zhang, Qian;Wang, Hong;Jin, Chen
背景：他汀类药物保护骨髓间充质干细胞(MSCs)免受恶劣微环境的影响，提高急性心肌梗死(AMI)后MSC移植的疗效，但其机制尚不清楚。此外，骨髓间充质干细胞在心肌梗死后的转分化潜能仍存在很大争议。RhoA/Rho相关的螺旋线圈形成激酶(ROCK)通路参与了急性心肌梗死后受损心脏的多个方面，并与STATE的“多效性”效应有关。本研究旨在探讨阿托伐他汀(ATV)是否通过抑制RhoA/ROCK通路及其下游分子细胞外调节蛋白激酶(ERK1/2)而促进MSCs的存活和治疗效果，并观察其体内的转分化潜能。急性心肌梗死后4周，ATV联合MSC治疗可改善心功能，缩小梗塞面积。AN促进了MSC的存活，表现为Y染色体基因表达的增加和Y染色体阳性细胞的增加；然而，没有观察到转分化标记。AN在体外和体内均抑制炎性细胞因子的产生，同时抑制ROCK和ERK的活性。焦磷酸香叶素(GGPP)可阻断ATV对缺氧/血清剥夺(H/SD)H9c2细胞的作用，而ROCK抑制剂法舒地尔则可模拟急性心肌梗死后ATV的作用。结论：ATV通过抑制RhoA/ROCK/ERK而改善脑梗塞后微环境，从而促进移植MSCs的存活和疗效。转分化可能不是骨髓间充质干细胞移植后心脏益处的原因。(C)2014年，爱思唯尔爱尔兰有限公司出版。
Background: Statins protect mesenchymal stem cells (MSCs) against the harsh microenvironment and improve the efficacy of MSC transplantation after acute myocardial infarction (AMI); however, the mechanism remains uncertain. Furthermore, the transdifferentiation potential of MSCs in the post-infarct heart remains highly controversial. The RhoA/Rho-associated coiled-coil-forming kinase (ROCK) pathway participates in many aspects of the damaged heart after AMI and related to the "pleiotropic" effects of station. This study aimed to explore whether atorvastatin (ATV) facilitates the survival and therapeutic efficacy of MSCs via the inhibition of RhoA/ROCK pathway and subsequently its downstream molecular extracellular regulated protein kinase (ERK1/2), and to investigate the transdifferentiation potential of MSCs in vivo.Methods and results: Female rats received myocardial injections of male rat MSCs 30 min after AMI. Four weeks after AMI, ATV combined with MSC treatment resulted in improved cardiac function and reduced infarct area. AN facilitated the MSC survival, as revealed by the increased expression of Y chromosomal genes and the increased number of Y chromosome-positive cells; however, no transdifferentiation markers were observed. AN inhibited the production of inflammatory cytokines both in vitro and vivo, accompanied by suppression of ROCK and ERK activities. Geranylgeranyl pyrophosphate (GGPP) abrogated the effects of ATV in the H9c2 cells under hypoxia/serum deprivation (H/SD), while the ROCK inhibitor fasudil mimicked the benefits of ATV after AMI.Conclusions: ATV improves the post-infarct microenvironment via RhoA/ROCK/ERK inhibition and thus facilitates the survival and efficacy of implanted MSCs. Transdifferentiation may be not responsible for the cardiac benefits that follow MSC transplantation. (C) 2014 Published by Elsevier Ireland Ltd.