Suppressor of cytokine signaling-3 is a biomechanical stress-inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways

The gp130 cytokine receptor activates a cardiomyocyte survival pathway duri ng the transition to heart failure following the biomechanical stress of pr essure overload. Although gp130 activation is observed transiently during t ransverse aortic constriction (TAC), its mechanism of inactivation is large ly unknown in cardiomyocytes. We show here that suppressor of cytokine sign aling 3 (SOCS3), an intrinsic inhibitor of JAK, shows biphasic induction in response to TAC. The induction of SOCS3 was closely correlated with STAT3 phosphorylation, as well as the activation of an embryonic gene program, su ggesting that cardiac gp130-JAK signaling is precisely controlled by this e ndogenous suppressor. In addition to its cytoprotective action, gp130-depen dent signaling induces cardiomyocyte hypertrophy. Adenovirus-mediated gene transfer of SOCS3 to ventricular cardiomyocytes completely suppressed both hypertrophy and antiapoptotic phenotypes induced by leukemia inhibitory fac tor (LIF). To our knowledge, this is the first clear evidence that these tw o separate cardiomyocyte phenotypes induced by gp130 activation lie downstr eam of JAK. Three independent signaling pathways, STAT3, MEK1-ERK1/2, and A KT activation, that are coinduced by LIF stimulation were completely suppre ssed by SOCS3 overexpression. We conclude that SOCS3 is a mechanical stress -inducible gene in cardiac muscle cells and that it directly modulates stre ss-induced gp130 cytokine receptor signaling as the key molecular switch fo r a negative feedback circuit for both myocyte hypertrophy and survival.