Absence of SOCS3 in the Cardiomyocyte Increases Mortality in a gp130-Dependent Manner Accompanied by Contractile Dysfunction and Ventricular Arrhythmias

Suppressor of cytokine signaling-3 (SOCS3) is a key negative-feedback regulator of the gp130 receptor that provides crucial signaling for cardiac hypertrophy and survival; however, an in vivo role of SOCS3 regulation on cardiac gp130 signaling remains obscure. We generated cardiac-specific SOCS3 kno...

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Published in:	Circulation (New York, N.Y.) Vol. 124; no. 24; pp. 2690 - 2701
Main Authors:	YAJIMA, Toshitaka, MUROFUSHI, Yoshiteru, DALTON, Nancy D, YAJIMA, Tomoko, YASUKAWA, Hideo, PETERSON, Kirk L, KNOWLTON, Kirk U, HANBING ZHOU, PARK, Stanley, HOUSMAN, Jonathan, ZHONG, Zhao-Hua, NAKAMURA, Michinari, MACHIDA, Mitsuyo, HWANG, Kyung-Kuk, YUSU GU
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott Williams & Wilkins 13-12-2011
Subjects:	Animals Arrhythmias, Cardiac - metabolism Arrhythmias, Cardiac - mortality Arrhythmias, Cardiac - physiopathology Biological and medical sciences Blood and lymphatic vessels Calcium - metabolism Calcium Signaling - physiology Cardiology. Vascular system Cardiomyopathy, Dilated - metabolism Cardiomyopathy, Dilated - mortality Cardiomyopathy, Dilated - physiopathology Coronary heart disease Cytokine Receptor gp130 - metabolism Disease Models, Animal Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Heart Heart Failure - metabolism Heart Failure - mortality Heart Failure - physiopathology Medical sciences Mice Mice, Knockout Myocardial Contraction - physiology Myocytes, Cardiac - metabolism NAV1.5 Voltage-Gated Sodium Channel Sodium Channels - metabolism STAT3 Transcription Factor - metabolism Suppressor of Cytokine Signaling 3 Protein Suppressor of Cytokine Signaling Proteins - deficiency Suppressor of Cytokine Signaling Proteins - genetics Heart failure ventricular arrhythmia Arrhythmia Cardiomyopathy Mortality SR Ca Cardiovascular disease Myocardial disease overload SOCS3 myofilament Ca Heart disease gp130 sensitivity
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Summary:	Suppressor of cytokine signaling-3 (SOCS3) is a key negative-feedback regulator of the gp130 receptor that provides crucial signaling for cardiac hypertrophy and survival; however, an in vivo role of SOCS3 regulation on cardiac gp130 signaling remains obscure. We generated cardiac-specific SOCS3 knockout (SOCS3 cKO) mice. These mice showed increased activation of gp130 downstream signaling targets (STAT3, ERK1/2, AKT, and p38) from 15 weeks of age and developed cardiac dysfunction from approximately 25 weeks of age with signs of heart failure. Surprisingly, SOCS3 cKO failing hearts had minimal histological abnormalities with intact myofibril ultrastructure. In addition, Ca(2+) transients were significantly increased in SOCS3 cKO failing hearts compared with wild-type hearts. We also found that Ser23/24 residues of troponin I were hypophosphorylated in SOCS3 cKO hearts before the manifestation of cardiac dysfunction. These data suggested the presence of abnormalities in myofilament Ca(2+) sensitivity in SOCS3 cKO mice. In addition to the contractile dysfunction, we found various ventricular arrhythmias in SOCS3 cKO nonfailing hearts accompanied by a sarcoplasmic reticulum Ca(2+) overload. To determine the contribution of gp130 signaling to the cardiac phenotype that occurs with SOCS3 deficiency, we generated cardiac-specific gp130 and SOCS3 double KO mice. Double KO mice lived significantly longer and had different histological abnormalities when compared with SOCS3 cKO mice, thus demonstrating the importance of gp130 signaling in the SOCS3 cKO cardiac phenotype. Our results demonstrate an important role of SOCS3 regulation on cardiac gp130 signaling in the pathogenesis of contractile dysfunction and ventricular arrhythmias.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0009-7322 1524-4539
DOI:	10.1161/circulationaha.111.028498