Abstract Body (Do not enter title and authors here): Introduction: During natural aging, physiological remodeling of the heart is a critical for the cardiovascular disease and heart failure. miR-30a-5p is related to kidney injury, cancer, and autoimmune diseases. However, whether miR-30a-5p has an effect in cardiac aging has yet to be explored.
Hypothesis: This study aimed to characterize the role and mechanism of action of miR-30a-5p in cardiac senescence.
Methods: We established miR-30a-5p knockout/overexpressing mouse model. Natural heart aging (18-months-old) and D-galactose-induced aging mouse model were established. The mechanism was explored in D-galactose- or 10-days-cultured cardiomyocytes.
Results: 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 overexpressed mice on natural- or D-galactose-induced heart aging. In vitro, using RNA-sequence and a series of molecular biology, the mechanism of miR-30a-5p-regulated 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, 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 showed effects similar to those observed in knockout mice. Notably, 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. Further evidence demonstrated that cardiac-specific TP53INP1 deficiency ameliorates miR-30a-5p knockout-aggravated cardiac dysfunction and heart senescence.
Conclusions: 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.