MiR‐203 improves cardiac dysfunction by targeting PARP1‐NAD+ axis in aging murine

Abstract

AbstractHeart aging is a prevalent cause of cardiovascular diseases among the elderly. NAD+ depletion is a hallmark feature of aging heart, however, the molecular mechanisms that affect NAD+ depletion remain unclear. In this study, we identified microRNA‐203 (miR‐203) as a senescence‐associated microRNA that regulates NAD+ homeostasis. We found that the blood miR‐203 level negatively correlated with human age and its expression significantly decreased in the hearts of aged mice and senescent cardiomyocytes. Transgenic mice with overexpressed miR‐203 (TgN (miR‐203)) showed resistance to aging‐induced cardiac diastolic dysfunction, cardiac remodeling, and myocardial senescence. At the cellular level, overexpression of miR‐203 significantly prevented D‐gal‐induced cardiomyocyte senescence and mitochondrial damage, while miR‐203 knockdown aggravated these effects. Mechanistically, miR‐203 inhibited PARP1 expression by targeting its 3′UTR, which helped to reduce NAD+ depletion and improve mitochondrial function and cell senescence. Overall, our study first identified miR‐203 as a genetic tool for anti‐heart aging by restoring NAD+ function in cardiomyocytes.