Abstract 1523: Pim-1 Regulates Cardiomyocyte Survival Downstream of Akt
Serine/threonine kinases including Pim-1 and Akt are involved in regulation of cellular proliferation and survival but, although Akt is known to be a critical kinase in myocardial signaling, the role of Pim-1 in this context has been overlooked. This study shows Pim-1 expression in the mouse heart is highest in postnatal myocardium and decreases with age, however Pim-1 expression can be induced in adult myocardium by cardiomyopathic challenge following infarction or pressure overload. Loss of Pim-1 by germline deletion results in decreased functional recovery and increased apoptosis following ischemia reperfusion injury. Pim-1 promotes survival signaling in cardiomyocytes with adenoviral-mediated overexpression of Pim-1 increasing expression of anti-apoptotic genes bcl-2, bcl-XL, mdm2, enhancing phosphorylation of BadS112 and diminishing p53 levels. Overexpression of Pim-1 is protective in cardiomyocytes challenged with doxorubicin-induced apoptosis. Multiple cardioprotective stimuli that induce Akt also induce Pim-1 expression, and Pim-1 induction is regulated by Akt activity. Loss of Pim-1 expression in knockout mice or inhibition by a dominant negative Pim-1 adenovirus results in increased expression and phosphorylation of Akt, supporting a role for feedback between Pim-1 and Akt signaling. These results, in combination with previous reports demonstrating potent inhibition of Pim-1 by canonical Akt inhibitors, indicate that Pim-1 is a critical effector downstream of Akt signaling. As such, effects previously attributed to Akt activity need to be reevaluated in the context of Pim-1.