Hu Xiaowu, Yang Junjie, Wang Ying, Zhang You, Ii Masaaki, Shen Zhenya, Hui Jie
Department of Cardiology of The First Affiliated Hospital, Soochow University Suzhou 215006, China ; Present address: Department of Cardiology of Xinyu People's Hospital Xinyu, Jiangxi Province, 338000, China.
Institute for Cardiovascular Science & Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University Suzhou 215006, China.
Int J Clin Exp Med. 2015 Sep 15;8(9):16991-7005. eCollection 2015.
Cell-based angiogenesis is a promising treatment for ischemic diseases; however, survival of implanted cells is impaired by the ischemic microenvironment. In this study, mesenchymal stem cells (MSCs) for cell transplantation were preconditioned with trimetazidine (TMZ). We hypothesized that TMZ enhances the survival rate of MSCs under hypoxic stimuli through up-regulation of HIF1-α.
Bone marrow-derived rat mesenchymal stem cells were preconditioned with 10 μM TMZ for 6 h. TMZ preconditioning of MSCs remarkably increased cell viability and the expression of HIF1-α and Bcl-2, when cells were under hypoxia/reoxygenation (H/R) stimuli. But the protective effects of TMZ were abolished after knocking down of HIF-1α. Three days after implantation of the cells into the peri-ischemic zone of rat myocardial ischemia-reperfusion (I/R) injury model, survival of the TMZ-preconditioned MSCs was high. Furthermore, capillary density and cardiac function were significantly better in the rats implanted with TMZ-preconditioned MSCs 28 days after cell injection.
TMZ preconditioning increased the survival rate of MSCs, through up-regulation of HIF1-α, thus contributing to neovascularization and improved cardiac function of rats subjected to myocardial I/R injury.
基于细胞的血管生成是治疗缺血性疾病的一种有前景的方法；然而，植入细胞的存活受到缺血微环境的损害。在本研究中，用于细胞移植的间充质干细胞（MSCs）用曲美他嗪（TMZ）进行预处理。我们假设TMZ通过上调缺氧诱导因子1-α（HIF1-α）来提高缺氧刺激下MSCs的存活率。
用10μM TMZ对大鼠骨髓来源的间充质干细胞预处理6小时。当细胞处于缺氧/复氧（H/R）刺激时，TMZ预处理的MSCs显著提高了细胞活力以及HIF1-α和Bcl-2的表达。但在敲低HIF-1α后，TMZ的保护作用消失。将细胞植入大鼠心肌缺血再灌注（I/R）损伤模型的缺血周边区3天后，经TMZ预处理的MSCs存活率很高。此外，在细胞注射28天后，植入经TMZ预处理的MSCs的大鼠的毛细血管密度和心脏功能明显更好。
TMZ预处理通过上调HIF1-α提高了MSCs的存活率，从而促进了新生血管形成并改善了心肌I/R损伤大鼠的心脏功能。
