Abstract 5359: Cardiac-Specific Deletion of SOCS3 Improved Cardiac Function and Survival after Acute Myocardial Infarction in Mice
Background: Although cytokines that activate JAK-STAT pathway have been shown to prevent the development of ventricular remodeling after AMI, little is known about the negative regulation of JAK-STAT pathway in this process. Suppressor of cytokine signaling 3 (SOCS3) is an intrinsic negative regulator of cytokine-induced STAT3 signaling that plays an important role in cardiomyocyte survival. Here, we determined whether STAT3 signaling and SOCS3 would play a role in the development of ventricular remodeling after AMI.
Methods and Results: We examined the activation of STAT3 and inductions of gp130 cytokines and SOCS3 in the wild-type mice (WT) hearts after AMI by western blot and real-time PCR (RT-PCR). RT-PCR revealed that gp130 cytokines including LIF were increased 2 days after AMI (p<0.01). Western blot revealed that STAT3 was phosphorylated and SOCS3 was induced in WT hearts after AMI. To investigate the role of STAT3 signaling and SOCS3 in ventricular remodeling, we generated cardiac-specific SOCS3 knockout mice (SOCS3-CKO). We found that smaller infarct size, less left ventricular end-diastolic dimension (LVEDD), improved ejection fraction (EF) in SOCS3-CKO compared to WT (infarct size, 36.9±3.5% vs. 57.5±2.3%, p<0.01; LVEDD, 4.4±0.2mm vs. 5.0±0.5mm, p<0.01; EF, 43.5±5.2% vs. 21.3±7.5%, p<0.01). Also the duration and intensity of STAT3 phosphorylation was greater in SOCS3-CKO than WT. Moreover, SOCS3-CKO showed greater survival rate than WT after AMI (p<0.01). To determine the mechanisms for reduced ventricular remodeling after AMI in SOCS3-CKO, we evaluated the apoptosis by TUNEL staining and western blot for caspase-3, and the angiogenesis by immunostaining for CD31 and RT-PCR for HGF and IGF. The number of TUNEL-positive cells (27.8±2.4% vs. 46.4±3.5%, p<0.01) and caspase3 expression after AMI were significantly less in SOCS3-CKO than the WT. The number of CD31 positive cells 14 days after AMI was significantly greater in SOCS-CKO than WT (61.4±6.1 cells/HPF vs. 51.6±5.0 cells/HPF, p<0.01). Expressions of HGF and IGF-1 were increased in SOCS3-CKO.
Conclusion: These results suggest that ventricular remodeling after AMI is less in SOCS3-CKO by enhancing STAT3 signaling, inhibiting cardiomyocyte apoptosis and promoting angiogenesis.