Abstract
BackgroundBone mesenchymal stem cell (BMSC) therapy has modest success in ischemic heart disease but has been limited by poor survival in diseased microenvironments. Cellular repressor of E1A-stimulated genes (CREG) can prevent BMSCs from apoptosis in vitro; however, the effects of CREG-modified BMSCs on ischemic heart disease and the related mechanism remain undefined. Therefore, we designed to study the cardioprotective effects of CREG overexpression in BMSCs (CREGBMSCs) after transplantation into infarcted heart of rats. MethodsIn vivo studies, 50μl PBS or 1.5×106NormBMSCs, GFPBMSCs or CREGBMSCs were implanted intramyocardially in myocardial infarction rat models. 3 or 14days later, cardiac function, fibrosis, apoptosis and angiogenesis were analyzed by echocardiography, masson, western blot and immunofluorescence staining, respectively. ELISA, western blot and matrigel assay were used in vitro to detect vascular endothelial growth factor (VEGF) secretion, signaling molecule expression, and angiogenic tube formation. ResultsIn vivo, prolonged cardiac function (14d LVEF: 50.87±0.94%; LVFS: 23.41±1.12%), decreased fibrosis (14d Fibrotic area: 27.37±1.03%) and apoptosis and increased angiogenesis were observed in CREGBMSCs, compared with other groups. In vivo and in vitro, VEGF secretion from CREGBMSCs was markedly enhanced. In vitro, angiogenic tube formation in CREGBMSC supernatants significantly increased. Moreover, CREG activated hypoxia-inducible factor-1α (HIF-1α), but not HIF-1β. Knockdown of HIF-1α with siRNA decreased VEGF secretion and angiogenic tube formation. Notably, CREG did not influence HIF-1α mRNA synthesis but inhibited the expression of Von Hippel–Lindau (VHL), a key protein that regulates HIF-1α degradation. ConclusionsThe CREGBMSC transplantation, directly or indirectly, may promote VEGF's anti-apoptosis and angiogenesis via the inhibition of VHL-mediated HIF-1α degradation, consequently protecting against myocardial infarction.
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