Abstract 1066: Cardiac-restricted Disruption of Supressor of Cytokine Signaling-3 Leads to Dilated Cardiomyopathy in a gp130 Independent Manner

Abstract

We recently reported that cardiac-restricted overexpression of suppressor of cytokine signaling-3 (SOCS3) markedly increases cardiac myocyte susceptibility to virus infection. This suggests that endogenous SOCS3 also has significant biological effect in the cardiac myocyte. To understand physiological role of SOCS3 in the cardiac myocyte, we generated cardiac-specific SOCS3 knockout mice. The mice were born at the expected Mendelian ratio, but developed cardiac dysfunction (%FS; wt: 45±2.6 vs. ko: 31±4.5, mean±SE, n=8, p=0.017, 5-month-old) estimated by echocardiogram from 5 months of age and died with signs of dyspnea by 7 months of age. Postmortem analysis revealed significant pleural effusions and ascites, consistent with the presence of heart failure. Histological analysis showed that the heart has a thin left and right ventricular walls with chamber dilatation; however, typical findings of a myopathic heart such as myocyte disarray, inflammation and fibrosis were only rarely observed. Ultrastructure analysis of the dilated heart samples showed intact myofibrils, mitochondria, intercalated discs and gap junctions, suggesting that the myocyte had non-structural abnormalities that led to functional impairment. Unexpectedly calcium transients in the isolated adult myocytes from the failing hearts were significantly increased as compared to those from age-matched normal hearts (Fura-2 intensity ratio 340/380 nm; wt: 0.44±0.01 vs. ko: 0.54±0.01, mean±SE, n=3, p<0.0002), suggesting the decreased calcium sensitivity of SOCS3 deficient myocytes. We also observed spontaneous ventricular tachycardia in the knockout mice by telemetry analysis. Since SOCS3 has been reported to be a crucial negative-feedback regulator of gp130 signaling in vivo, we sought to determine whether the phenotype is due to overactivation of cardiac gp130 signaling. While gp130 downstream signaling such as STAT3, ERK and AKT pathways were significantly activated in the knockout heart, cardiac-specific knockout of both gp130 and SOCS3 did not rescue the dilated cardiomyopathy phenotype. Conclusion: These results indicate that a gp130-independent mechanism is responsible for the dilated cardiomyopathy that occurs in SOCS3 deficient hearts.