Abstract 13838: Pim Deletion Promotes Premature Cardiac Cellular Senescence
Rationale: Cardiac aging is a multifactorial process characterized by cellular senescence within cardiomyocytes and the cardiac stem cell population. The senescent phenotype is accompanied by changes in mitochondrial function and biogenesis that impair energy production. Energy intensive processes of cell growth and proliferation are dependent upon mitochondrial functional activity that impacts mammalian target of rapamycin (mTOR) signaling, which typically declines with senescence. Pim-1 kinase is cardioprotective and antagonizes the phenotypic characteristics of aging in the myocardium, therefore consequences of diminished Pim kinase activity upon myocardial aging and senescence were examined.
Objective: Demonstrate senescence is accelerated by loss of Pim kinase, leading to premature myocardial aging in conjunction with characteristic alterations of mitochondrial function and mTOR signaling.
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 p53 and p16 are present in PTKO hearts at 2 months. Increased p16 expression is consistent with observed induction of Ets-1, a transcription factor that activates p16 transcription, in PTKO hearts. Levels of c-myc, Id1, and Id2, positive transcriptional regulators of the cell cycle, are decreased in PTKO hearts. Impaired cardiac function was evident by echocardiographic analyses of PTKO mice at 9 months. Furthermore, PTKO mice have enlarged myocytes and reduced number of cardiomyocytes at 2 months. Mitochondrial DNA content and mitochondrial biogenesis genes were reduced in PTKO mice at 1 month of age coupled with disfigured mitochondrial morphology compared to controls. Furthermore, levels of phosphorylated AMPK, the cellular energy sensor, were elevated in PTKO mice at 1 month and persisted at 1 year. Consequently, high levels of phospho AMPK shutdown mTOR activity as evidenced by diminished levels of phospho ribosomal S6.
Conclusion: Senescence and survival are essential issues in the aging heart. Pim1 is an ideal molecular therapeutic approach which can inhibit progression toward a senescent phenotype and promote survival signaling.
- © 2012 by American Heart Association, Inc.