Bone marrow mesenchymal stem cell-derived vascular endothelial growth factor attenuates cardiac apoptosis via regulation of cardiac miRNA-23a and miRNA-92a in a rat model of myocardial infarction

Bone marrow-mesenchymal stem cell (BM-MSC) therapy improves the recovery of cardiac function after myocardial infarction (MI); however, the underlying molecular mechanisms are not completely understood. Recent studies have shown that microRNAs (miRNAs) modulate the pathophysiology of cardiovascular diseases. Here, we investigated the mechanisms underlying the effects of BM-MSC-derived paracrine factors and cardiac miRNAs on myocardial regeneration after MI. In our study, MI was induced by permanent ligation of the left anterior descending (LAD) coronary artery. BM-MSCs transplanted in infarcted rats significantly downregulated the expression of miRNA-23a and miRNA-92a and inhibited apoptosis in the myocardium. An in vitro experiment showed that supernatant from BM-MSCs cultured under hypoxia contained higher levels of vascular endothelial growth factor (VEGF) than that from BM-MSCs under normoxia. In addition, inhibition of miRNA-23a and miRNA-92a reduced cardiac apoptosis. Moreover, the VEGF-containing BM-MSC supernatant inhibited miRNA-23a and miRNA-92a expression and reduced apoptotic signaling in cardiomyocytes under hypoxia. These effects were inhibited when the supernatant was treated with neutralizing antibodies against VEGF. Our results indicate that the paracrine factor, VEGF, derived from transplanted BM-MSCs, regulated the expression of miRNAs such as miRNA-23a and miRNA-92a and exerted anti-apoptotic effects in cardiomyocytes after MI.骨髓间充质干细胞（Bone marrow-mesenchymal stem cell, BM-MSC）疗法可改善心肌梗死（Myocardial infarction, MI）后的心功能恢复，但其潜在分子机制尚未完全阐明。现有研究表明，微小RNA（microRNAs, miRNAs）可调控心血管疾病的病理生理过程。本研究旨在探究BM-MSC来源的旁分泌因子与心脏miRNAs对心肌梗死后心肌再生的作用机制。本研究通过永久性结扎左前降支（Left anterior descending coronary artery, LAD）冠状动脉构建心肌梗死大鼠模型。向造模成功的大鼠移植BM-MSC后，可显著下调心肌组织中miRNA-23a与miRNA-92a的表达水平，并抑制心肌细胞凋亡。体外实验结果显示，缺氧培养的BM-MSC上清液中血管内皮生长因子（Vascular endothelial growth factor, VEGF）的含量显著高于常氧培养的BM-MSC上清液。此外，抑制miRNA-23a与miRNA-92a的表达可减轻心肌细胞凋亡。进一步研究发现，含VEGF的BM-MSC上清液可在缺氧条件下抑制心肌细胞中miRNA-23a与miRNA-92a的表达，并减弱心肌细胞的凋亡信号通路激活。若使用抗VEGF中和抗体处理该上清液，则上述保护效应会被完全阻断。本研究结果表明，移植的BM-MSC通过其旁分泌因子VEGF，调控miRNA-23a与miRNA-92a等微小RNA的表达，进而在心肌梗死后的心肌细胞中发挥抗凋亡的保护作用。