Abstract 16287: Genetic Deletion of Pim Causes Premature Cardiac Senescence
Rationale: Cardiac aging is defined as increased cellular senescence and loss of survival signaling within cardiomyocytes and the cardiac stem cell population. To prevent myocardial, aging it is important to reverse the characteristic aging phenotype. Pim-1 is a cardioprotective kinase downstream of AKT, and has been shown to be pro-proliferative and anti-apoptotic. Pim-1 mediated antagonism of myocardial aging will lead to a decrease in cardiac senescence, maintain contractile performance, and prolong the lifespan of an organism.
Objective: Demonstrate that myocardial senescence is antagonized by Pim-1 mediated signaling and loss of Pim-1 activity leads to premature aging of the myocardium and associated decline in cardiac performance.
Methods and Results: Pim Triple KnockOut (PTKO) mice, in which all three isoforms of Pim are genetically deleted, develop premature phenotypic hallmarks of myocardial senescence. Elevated levels of the tumor suppressor p53 and senescence marker p16 are present in hearts of PTKO mice at two months of age as seen by western blot and confocal microscopy. Increased p16 expression is consistent with observed induction of Ets-1, a transcription factor that activates p16 transcription in PTKO cardiac samples by western blot. Levels of Id1 and Id2, positive transcriptional regulators of the cell cycle, are decreased in hearts of PTKO mice. Hemodynamic analyses reveal impaired cardiac function in PTKO mice at two months of age. Conversely, cardiac specific overexpression of Pim1-kinase attenuates the senescent phenotype. Hypoxia treatment of neonatal rat cardiomyocytes infected with Pim-1 encoding adenovirus results in reduction of p16 accumulation as seen by qRT-PCR. Pim-1 overexpression increases expression of c-myc, thereby upregulating Id2 and inhibits p16 induced senescence. Cardiac Pim-1 transgenic mice show a delay in the onset of senescence as evidenced by decreased frequency of p16 positive cells in the myocardium by confocal microscopy.
Conclusion: Pim-1 inhibits cardiac senescence and is important for maintaining cardiac function. Therefore, selective manipulation of Pim-1 should be pursued as a therapeutic target to promote and extend myocardial cellular lifespan and function.
- © 2011 by American Heart Association, Inc.