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 during the transition to heart failure following the biomechanical stress of pressure overload. Although gp130 activation is observed transiently during transverse aortic constriction (TAC), its mechanism of inactivation is largely unknown in cardiomyocytes. We show here that suppressor of cytokine signaling 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, suggesting that cardiac gp130-JAK signaling is precisely controlled by this endogenous suppressor. In addition to its cytoprotective action, gp130-dependent signaling induces cardiomyocyte hypertrophy. Adenovirus-mediated gene transfer of SOCS3 to ventricular cardiomyocytes completely suppressed both hypertrophy and antiapoptotic phenotypes induced by leukemia inhibitory factor (LIF). To our knowledge, this is the first clear evidence that these two separate cardiomyocyte phenotypes induced by gp130 activation lie downstream of JAK. Three independent signaling pathways, STAT3, MEK1-ERK1/2, and AKT activation, that are coinduced by LIF stimulation were completely suppressed by SOCS3 overexpression. We conclude that SOCS3 is a mechanical stress-inducible gene in cardiac muscle cells and that it directly modulates stress-induced gp130 cytokine receptor signaling as the key molecular switch for a negative feedback circuit for both myocyte hypertrophy and survival.
Yasukawa
H
H
University of California San Diego-Salk Program in Molecular Medicine, UCSD Institute of Molecular Medicine, and Department of Medicine, University of California San Diego, La Jolla, California 92093-0613C, USA.
Hoshijima
M
M
Gu
Y
Y
Nakamura
T
T
Pradervand
S
S
Hanada
T
T
Hanakawa
Y
Y
Yoshimura
A
A
Ross
J
J
Chien
K R
KR
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D006332:Cardiomegaly; D002470:Cell Survival / Q000502:physiology*; D050822:Cytokine Receptor gp130; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors
D015703:Antigens, CD; C494200:Il6st protein, mouse; D008562:Membrane Glycoproteins; D011506:Proteins; D012097:Repressor Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D050822:Cytokine Receptor gp130