Pim-1 mediated signaling during the process of cardiac remodeling following myocardial infarction in ovine hearts

The serine/threonine kinase Pim-1 was recently identified as a cardiomyocyte survival regulator downstream of Akt. The present study aims to examine Pim-1 activity and its association with the post MI remodeling myocardium in a clinically relevant large animal model. Apical myocardial infarction of approximately 25% left ventricular mass was created in an ovine model. Regional post-infarction deformation of the left ventricle was monitored by sonomicrometry and quantified using areal remodeling strain (i.e., areal expansion). Myocardial tissues were harvested at 12weeks from the adjacent and remote regions of the infarct for analysis of Pim-1 mediated survival signaling proteins as well as apoptotic activity. The cDNA coding sequences of two ovine Pim-1 kinase isoforms, 44 and 33kDa, were identified. Both isoforms were detected in heart tissue and the overall Pim-1 expression was found to be tightly controlled at multiple molecular levels. Pim-1 as well as the Pim-1 mediated survival signaling proteins Bcl-2, Bcl-xL, and phospho-Bad (Ser112) were upregulated in the adjacent region at 12weeks post-infarction and their expression correlated positively with the degree of the remodeling, which was accompanied by significant upregulations of the PP2A/BAD mediated apoptotic signaling proteins. However these upregulations were imbalanced, such that p-BAD (Ser112)/BAD decreased in the adjacent region of the infarcted hearts. Apoptotic activity also increased with remodeling strain. Despite an observed intrinsic upregulation of survival proteins, the imbalanced activation of apoptotic pathways resulted in evident apoptosis in the adjacent region.