Abstract 12113: STAT1 Transcription Factor is Required for the Delayed Protection Against Cardiomyocyte Apoptosis by Ischemic Preconditioning
Apoptosis accounts for significant cardiomyocyte loss during myocardial infarction. Although STAT1 is known to play a predominantly proapoptotic role in many cells and tissues, the role of STAT1 signaling in the late phase of ischemic preconditioning (PC) remains unclear. In this study, we used STAT1 knockout (KO) mice to definitively determine whether STAT1 is necessary for the antiapoptotic effects of ischemic late PC. Wild-type (WT) and STAT1 KO mice (n=5-6/group) underwent a 20-min coronary occlusion followed by 3 h of reperfusion with or without six cycles of 4-min coronary occlusion/reperfusion 24 h earlier. In WT mice, ischemic PC increased tyrosine- and serine-phosphorylation of nuclear STAT1, and increased STAT-GAS-DNA binding activity (701±40% vs. nonpreconditioned WT controls) 30 min later. Ischemic PC also mitigated the increase in cleaved (active) caspase-3 (immunohistochemistry) and cardiomyocyte apoptosis (in situ hairpin-1 ligation assay; 4±0.8% vs. 12±1.3% in nonpreconditioned WT controls). Targeted disruption of the STAT1 gene completely eliminated STAT1 and did not affect the expression and phosphorylation of STAT3. However, STAT1 deletion inhibited the ischemic PC-induced increase in the STAT-GAS-DNA binding activity. Deletion of STAT1 also inhibited the protective effects of ischemic PC against caspase-3 activation and apoptosis (Figure). Further, ischemic PC-induced delayed upregulation of several antiapoptotic proteins, including Mcl-1, Bcl-xL, and c-IAP1, was abrogated in STAT1 KO mouse hearts. We conclude that STAT1 is necessary for the delayed protection against cardiomyocyte apoptosis afforded by ischemic PC. These data also indicate that STAT1 is an obligatory factor in the upregulation of Mcl-1 and Bcl-xL, molecules that regulate mitochondrial apoptosis, and c-IAP1 that directly inhibits caspase-3 activation.
- © 2013 by American Heart Association, Inc.