UCLA

Previous studies show mammalian cardiomyocytes will undergo depressed proliferation and induced apoptosis shortly after birth, but vary to different degrees in two ventricles. p38 MAP kinase (p38) was indicated to be a contributor to this variation, but with unclear functioning mechanism. For a better understanding, we conducted in vivo study using p38α/β cardiac specific conditional knockout mice model, and in vitro experiments in neonatal rat ventricular cardomyocytes. Both models show inhibiting p38α/β causes an increased expression of inositol-requiring protein 1 alpha (IRE1α) and x-box binding protein 1 (XBP1) splicing in cardiomyocytes, but different pro-survival responses at different postnatal days: elevated mitosis at P3 while reduced apoptosis at P1, while both responses were found in vitro. Overexpressing IRE1α in vitro generates similar pro-survival effect to p38 inhibition, whereas knocking down XBP1 significantly blunts p38-inhibition-induced proliferation. Thus, we raise a chamber-specific model in which p38 regulates postnatal heart proliferation/apoptosis via inhibiting IRE1α.