Abstract
Heart senescence is critical for cardiac function. This study aimed to characterize the role and mechanism of action of miR-30a-5p in cardiac senescence. miR-30a-5p was downregulated in aged mouse hearts and neonatal rat cardiomyocytes (NRCMs). In vivo, using a combination of echocardiography and different molecular biological approaches, we investigated the role of miR-30a-5p knockout or overexpression in natural- or D-galactose-induced heart aging in mice. In vitro, using RNA sequencing and a series of molecular biology methods, the mechanism by which miR-30a-5p regulates cardiac senescence was explored in cardiomyocytes. miR-30a-5p knockout mice showed aggravated natural- or D-galactose-induced heart aging compared to wild-type littermate mice, with significantly decreased heart function, an increased number of γH2AX-positive cells, reduced telomere length, and upregulated p21 and p53 expression. Cardiac-specific knockdown of miR-30a-5p using adeno-associated virus 9 in D-galactose-induced senescent wild-type mice resulted in effects similar to those observed in knockout mice. Notably, the overexpression of miR-30a-5p in wild-type murine hearts alleviated D-galactose-induced heart senescence by improving heart function, increasing telomere length, decreasing the number of γH2AX-positive cells, and downregulating p53 and p21 expression. This was confirmed in D-galactose-treated or naturally aged NRCMs. Mechanistically, TP53INP1 was identified as a target of miR-30a-5p by mediating the SUMOylation of TP53INP1 and its translocation from the cytoplasm to the nucleus to interact with p53. Furthermore, this study demonstrated that cardiac-specific TP53INP1 deficiency ameliorates miR-30a-5p knockout-aggravated cardiac dysfunction and heart senescence. This study identified miR-30a-5p as a crucial modulator of heart senescence and revealed that the miR-30a-5p-TP53INP1-p53 axis is essential for heart and cardiomyocyte aging.