Abstract
Recent studies have provided increasing evidence that microRNAs (miR) play an important role in ischemic heart repair. We have previously reported that GATA-4 gene transfection increases mesenchymal stem cells (MSC) mediated cardioprotection. In this study, we investigated whether the cardioprotective effect of MSC overexpressing GATA-4 was associated with regulation of miR. Methods and Results: MSC were transduced with GATA-4 (MSC GATA-4 ) using the murine stem cell virus (pMSCV) retroviral expression system, control cells were transduced with empty vector (MSC Null ). The expression of miR in MSC was assessed by miR microarray and quantitative real-time PCR. Primary cultured cardiomyocytes (CM) were obtained from neonatal rat ventricles. Hypoxic treatment was used to mimic ischemic injury. The cardioprotection in vitro of MSC GATA-4 was examined through measurements of Lactate dehydrogenase release, MTT intake, and Annexin-V staining. To further determine the effect of MSC GATA-4 on ischemic myocardium, MSC were injected into the peri-infarct region in myocardial infarction model in SD rats developed by ligation of the left anterior descending coronary artery (LAD). Overexpression of GATA-4 regulated several miR expression in MSC, especially, downregulation of miR-15b, miR-16, and miR-195 which belong to miR-15 family, and upregulation of miR-221/222. MSC GATA-4 markedly protected CM against ischemic injury. Quantitative fluorescence in situ hybridization and immunostaining results showed that miR-221 as well as Bcl-w and VEGF, two proteins of target genes of miR-15 family, were transferred from MSC to CM. Gap junctions were observed between CM and MSC in a co-culture system. MSC GATA-4 treated animals showed significantly improved cardiac function by echocardiography. Furthermore, histological studies revealed reduced infarction size. Conclusions: Overexpression of GATA-4 regulates miR expression in MSC, which plays an important role in protection of myocytes from ischemia.
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