Abstract 3059: Absence of SOCS3 Regulation on gp130 Signaling in the Cardiac Myocyte Results in Increased Voltage-gated Sodium Channel (SCN5A) Current, Arrhythmogenicity and Cardiomyopathy
Suppressor of cytokine signaling-3 (SOCS3) is a key negative-feedback regulator of gp130 signaling. To determine the role of SOCS3 regulation on gp130 signaling in the heart, we generated cardiac-specific SOCS3 knockout mice (SOCS3 cKO). The mice developed severe dilated cardiomyopathy (DCM) with arrhythmias such as sustained ventricular tachycardia. The failing hearts did not have typical histological findings such as myocyte necrosis, inflammation and fibrosis. Ultrastructure of the myofibrils, nucleus and mitochondria were also intact. This indicated the presence of non-structural abnormalities inducing cardiac dysfunction in SOCS3 cKO. The abnormalities were prevented when the SOCS3 cKO were bred with gp130 cKO mice. This demonstrated the dependence of SOCS3 cKO phenotype on gp130 signaling. In isolated SOCS3-deficient myocytes, we found significantly increased Ca2+ transients in spite of contractile dysfunction compared to those in wild-type myocytes (Fura-2 intensity ratio 340/380 nm; ko: 0.183±0.021 vs. wt: 0.12±0.012, mean±SE, n=15, p=0.026). In contrast, the time constant of [Ca2+]i decline was significantly prolonged (ko: 0.235±0.019 vs. wt: 0.16±0.012, mean±SE (msec), n=15, p=0.0072) with delay of the myocyte relaxation. The [Ca2+]i decline abnormalities with the increased Ca2+ transient suggested the decreased activity of Na+-Ca2+ exchanger (NCX) rather than sarcoplasmic reticulum Ca2+ uptake in SOCS3 cKO. As a factor that can affect NCX and Ca2+ transient, we found increases in SCN5A mRNA and protein with a significant increase in voltage-gated Na+ current (wt: −167±23.7 vs. ko: −310±31.6, at test potential −70mV, mean±SE (pA/pF), n=12, p=0.0015) in SOCS3-deficient myocytes. gp130 stimulation with cardiotrophin-1 increased SCN5A mRNA in SOCS3-deficient but not wild-type myocytes. This indicated that SCN5A upregulation with gp130 stimulation only occurred in the absence of SOCS3. In conclusion, unregulated gp130 activation without SOCS3 increases voltage-gated Na+ current in cardiac myocytes, which induces diastolic dysfunction and arrhythmogenicity. Considering the strong association between SCN5A mutations and DCM in human, abnormalities of SOCS3 regulation should be considered in the pathogenesis of DCM.
This research has received full or partial funding support from the American Heart Association, National Center.