Abstract 3867: Pim-1 Kinase Plays an Essential Role in Development of Diabetic Cardiomyopathy
Diabetic cardiomyopathy, independent of coronary artery disease, is a frequent cause of heart failure. The disease has an insidious onset, manifesting with isolated diastolic dysfunction, which progresses with time to global heart failure. The present study was aimed to evaluate the pathogenetic role of the Proviral integration site for Moloney murine leukemia virus 1 (Pim-1), a member of the serine/threonine protein kinase family, which plays a major role in cardiomyocyte survival. Streptozocin-induced CD1 diabetic (DM) mice and age-matched controls were monitored by Vevo high resolution echocardiography. At 4 weeks, DM mice showed reduced diastolic function, which further deteriorated at 20 weeks combining with contractile dysfunction and left ventricular dilatation. Molecular analysis demonstrated a 35±8% reduction in Pim-1 protein levels (P<0.05 vs. control) along with 360±45% increase in cleaved caspase-3 expression (P<0.001) at the end of 8 weeks of DM. Microarray analysis at 12 weeks confirmed the modulation of genes associated with Pim-1 survival pathway (downregulation of Pim-1 activators such as STAT3 and Akt and upregulation of Pim-1 inhibitor PP2A). Further, microRNA (miRNA) analysis showed a 3 fold increase in the miRNA-1 (P<0.0001 vs. control), a known inhibitor of Pim-1 expression. Moreover, stabilization of Pim-1 using the PP2A inhibitor Okadaic acid (10nM) reduced the high glucose-induced apoptosis of cardiomyocytes by 26±5% (P<0.05) through phosphorylation of Bad and activation of cell survival Bcl-2 protein. These results demonstrate the contribution of different modulators in the downregulation of Pim-1 prosurvival mechanism. Pim-1 may represent a therapeutic target for the treatment of diabetic cardiomyopathy.