Abstract 12143: STAT1 Signaling is Critical for the Infarct-Sparing Effects of Late Ischemic Preconditioning
The results from pharmacologic inhibition of the JAK-STAT pathway with Jak2 inhibitor AG-490 suggest that STAT1/STAT3 activation is necessary for the delayed protective effects of ischemic preconditioning (PC) against infarction. However, the specific role of STAT1 in this process remains unclear. In this study, we used STAT1 knockout (KO) mice to address this issue. Wild-type (WT) and STAT1 KO mice (n=5-10/group) underwent a 20-min coronary occlusion followed by 24 h of reperfusion with or without 6 cycles of coronary occlusion/reperfusion 24 h earlier. In control (nonpreconditioned) WT mice, the infarct size averaged 55±4.6% of the region at risk. In preconditioned WT mice, infarct size was reduced to 34±6.4%, indicating a robust late PC effect. In control STAT1 KO mice, infarct size (46±4.4%) was not different from control WT mice, indicating that the deletion of STAT1 has no significant effect on infarct size. However, in preconditioned STAT1 KO mice, infarct size was not reduced (57±4.5%), indicating complete abrogation of infarct-sparing effects. Targeted disruption of the STAT1 gene eliminated STAT1 and did not affect expression and phosphorylation of STAT3. Ischemic PC also upregulated myocardial expression of several cardioprotective proteins, including inducible nitric oxide synthase (iNOS; 205±20% vs. control), cyclooxygenase-2 (COX-2; 399±38% vs. control), heme oxygenase-1 (HO-1; 238±10% vs. control), and extracellular superoxide dismutase (ec-SOD; 524±9.2% vs. control) 24 h later. STAT1 deletion almost completely inhibited the ischemic PC-induced upregulation of iNOS, COX-2, HO-1, and ec-SOD observed in WT mice. In conclusion, our data provide the first demonstration that STAT1 is obligatorily required for the protection against infarction afforded by late ischemic PC. Mechanistically, these data indicate a critical role of STAT1 in delayed upregulation of multiple cardioprotective proteins after ischemic PC.
- © 2013 by American Heart Association, Inc.