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

摘要

Heart 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.

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