Abstract 18726: Heme Oxygenase-1 (HO-1) Regulates microRNA-122-5p and -365-3p against Apoptosis in Cardiac Progenitor Cell (CPC) Therapy

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Abstract

Although overexpression of HO-1 in CPCs enhances the efficacy of cell therapy for attenuating LV dysfunction and remodeling after myocardial infarction (MI), its mechanism is unknown. To this end, lin-/c-kit+ CPCs were isolated from wild-type (WT), HO-1 transgenic (TG) or knockout (KO) mouse hearts and then characterized by FACS. Mice received 1x105 CPCs 48 h after a 60-min MI via intramyocardial injection; 24 h later, cells undergoing apoptosis in the mouse heart post-MI were detected by TUNEL staining. As showed in Figure, overexpression of HO-1 gene in CPCs by transgenic approach significantly decreased the number of TUNELPOS nuclei in HO-1TG CPC-treated hearts compared with that in vehicle, WT, or HO-1KO CPC-treated hearts, indicating anti-apoptotic effect of HO-1 on CPC survival at first 24 h after cell transplantation. Furthermore, the mouse heart post-MI was collected 6 h after CPC treatment; total microRNAs were isolated from the risk region to detect the expression profile of 84 mature microRNAs highly relevant to apoptosis by miScript microRNA real-time PCR Array approach. Among the 84 detected microRNAs, the expression level of microRNA-122-5p, which inhibits Bcl-w mRNA expression, an anti-apoptotic Bcl-2 family member, was significantly decreased in the HO-1TG CPC-treated hearts (-3.2-fold vs. WT CPC group, -4.3-fold vs. HO-1KO CPC group, Fig) whereas the expression level of microRNA-365-3p, which targets BAX, an apoptosis-promoting gene, was markedly reduced in the hearts treated with CPCs in which HO-1 gene was knocked out (-25-fold vs. WT or HO-1TG CPC group, Fig). These results indicate that overexpression of HO-1 gene in CPCs reduces myocardial apoptosis by modulating the expression of microRNAs that govern pro-apoptotic and anti-apoptotic gene expression in the infarcted heart after cell treatment. The data provide a potential therapeutic approach for promoting myocardial reparation via modification of CPCs with cytoprotective HO-1 gene.

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