Abstract 15359: Reduction of Myocardial Ischemia-Reperfusion Injury in Cardiac-Specific SOCS3 Deficient Mice by Activating Cardioprotective Signaling Pathways
Background: Although cytokines that activate JAK-STAT pathway have been shown to prevent the myocardial ischemia/reperfusion (I/R) injury, little is known about the negative regulation of JAK-STAT pathway in the development of I/R injury. We have previously shown that suppressor of cytokine signaling 3 (SOCS3) is an intrinsic negative regulator of cytokine-induced STAT3 activation and that ectopic expression of SOCS3 to ventricular cardiomyocytes suppressed antiapoptotic phenotypes induced by cytokines including leukemia inhibitory factor (LIF). We hypothesized that cardiac-specific deletion of SOCS3 would prevent myocardial I/R injury by enhancing STAT3 signaling pathway.
Methods and Results: In vivo myocardial I/R was created in 8-week-old mice by 1-hr ligation of the left anterior descending coronary artery, followed by indicated time of reperfusion. We examined the activation of STAT3 and inductions of hematopoietic or gp130 cytokines and SOCS3 in the wild-type (WT) mice hearts during I/R injury by western blot and real time PCR. Real-time PCR revealed that cytokines including G-CSF, interleukin-11 and LIF were markedly increased 1-hr after reperfusion (G-CSF; 64.2 fold, p<0.01, interleukin-11; 8.3 fold, p<0.01, LIF; 18.7 fold, p<0.01). The phosphorylation of STAT3 was faint 1-hr after ischemia, marked 20 minutes after reperfusion and suppressed 3-hr after reperfusion. This transient activation of STAT3 was closely correlated with the induction of SOCS3, suggesting that STAT3 activation is negatively regulated by SOCS3 during I/R injury. To investigate the role of STAT3 signaling and SOCS3 during I/R injury, we generated cardiac-specific SOCS3 knockout mice (SOCS3-KO). SOCS3-KO had a 33% reduction in myocardial infarct size and a preservation of LV fractional shortening after I/R compared with WT mice (p<0.01). The phosphorylations of cardioprotective signaling molecules such as STAT3, AKT and ERK1/2 were much greater in SOCS3-KO than WT mice.
Conclusion: These results suggest that myocardial I/R injury is prevented in SOCS3-KO by augmenting multiple cardioprotective signaling pathways.
- © 2010 by American Heart Association, Inc.