Targeting Cardiomyocyte PCNA and POLD1 Prevents Pathologic Myocardial Hypertrophy

作者：Soumojit Pal, Michael S. Glennon, Benjamin R. Nixon, Ethan J. Chetkof, Puneeth Shridhar, C. Kathiresan, Morgan B. Glasser, Christina Waldron, Lanping Guo, Nicolas G. Clavere, Dipanjan Banerjee, Jenny H. Kim, Jason R. Becker · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.124.325647 · 被引用次数：3 · 研究领域：Cardiomyopathy and Myosin Studies、Congenital heart defects research、Cardiac Fibrosis and Remodeling

BACKGROUND: Activation of cell cycle regulatory pathways has been detected during pathological cardiomyocyte growth. However, it has remained unclear whether DNA synthesis pathways play a direct role in cardiomyocyte hypertrophy. We previously discovered in a mouse model of hypertrophic cardiomyopathy that there was increased DNA synthesis, which led to cardiomyocyte endoreplication and replication stress–induced DNA damage. We hypothesized that targeting cardiomyocyte endoreplication pathways could reduce pathological myocardial hypertrophy. METHODS: We utilized murine models of hypertrophic cardiomyopathy secondary to mutations in cardiac Mybpc3 (myosin-binding protein C3) −/− or Myh6 (myosin heavy chain 6) R404Q and transverse aortic constriction as a model of pressure overload cardiomyocyte hypertrophy. We manipulated in vivo p21 (cyclin dependent kinase inhibitor 1) protein levels using transgenic mouse models or viral transduction. Cardiomyocyte endoreplication was assessed using flow cytometry and immunohistochemistry of cardiomyocyte nuclei. We also utilized proteomics, proximity ligation assays, and human-induced pluripotent stem cell–derived cardiomyocytes. RESULTS: We discovered that p21 protein peaked during the early stages of hypertrophic growth in both murine hypertrophic cardiomyopathy models and a pressure overload hypertrophy model. Using genetic manipulation of p21 expression, we discovered that cardiomyocyte endoreplication and hypertrophic growth were neg...