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The cardioprotective effects of Pim-1 kinase

  • Author(s): Muraski, John A.
  • et al.
Abstract

Cardioprotection through cell survival kinase signaling endures as a highly significant avenue of cardiac research. Herein we demonstrate the proto-oncogenic kinase Pim-1 is developmentally regulated and reappears after pathological injury in human and mouse myocardium. Overexpression of Pim-1 induces protective signaling molecules, and inhibits doxorubicin and deoxyglucose induced apoptosis in cardiomyocytes. IGF-1 mediated induction of Pim-1 expression is mediated by AKT and Pim-1 expression is necessary for AKT mediated cardioprotection. Pim-KO hearts are more susceptible to pathological injury by TAC, MI, and sI/R, exhibit more senescent myocytes and decreased ANP levels despite increased AKT expression and activation. Overexpression of inactive Pim-1 in the myocardium induces a potent dilated cardiomyopathy by 19 weeks of age with increased apoptosis and fibrosis. In contrast, cardiac-specific overexpression of Pim-1 protects the myocardium from pathological injury following TAC and MI, increasing asymmetric division of cardiac stem cells and increasing myocardial regeneration and function. Additionally, we find Pim-KO animals have a temporal lag in calcium transients with decreased SERCA expression, while Pim-1 overexpression induces a 4.89-fold increase in levels of the calcium handling protein. Pim-1 overexpression in NRCM cultures induces dedifferentiation with reemergence of cardiac progenitor cell proteins. Thus Pim-1 is a potent cardioprotective molecule operating downstream of AKT

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