SOCS1/JAB Likely Mediates the Protective Effect of Cardiotrophin-1 Against Lipopolysaccharide-Induced Left Ventricular Dysfunction In Vivo

• Published in: Circulation Journal Vol. 69; no. 11; pp. 1412 - 1417
• Main Authors: Tanimoto, Keiji, Saito, Yoshihiko, Hamanaka, Ichiro, Kuwahara, Koichiro, Harada, Masaki, Takahashi, Nobuki, Kawakami, Rika, Nakagawa, Yasuaki, Nakanishi, Michio, Adachi, Yuichiro, Shirakami, Gotaro, Fukuda, Kazuhiko, Yoshimura, Akihiko, Nakao, Kazuwa
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Circulation Society 2005
• Subjects: Animals; Cardiotrophin-1; Cells, Cultured; Cytokines - administration & dosage; Gene Expression Regulation; Lipopolysaccharide; Lipopolysaccharides - toxicity; Male; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Rats; Rats, Wistar; Sepsis; Signal Transduction - drug effects; SOCS1/JAB; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins - biosynthesis; Ventricular Dysfunction, Left - chemically induced; Ventricular Dysfunction, Left - drug therapy; Ventricular Dysfunction, Left - metabolism
• ISSN: 1346-9843; 1347-4820
• DOI: 10.1253/circj.69.1412

Background Suppressor of cytokine signaling 1 (SOCS1) is a negative regulator of cytokine signaling whose expression is induced in the rat heart by cardiotrophin-1 (CT-1). Sepsis-induced myocardial depression results from the expression of inducible nitric oxide synthase (iNOS) evoked by inflammatory cytokines. Methods and Results The effect of CT-1 on lipopolysaccharide (LPS)-induced cardiac dysfunction was examined in a rat model of sepsis. In the absence of CT-1, LPS (1 mg/kg ip) elicited a reduction of systolic function and dilation of the ventricular cavity within 3-6 h after administration. These physiological effects were accompanied by increased ventricular phosphorylation of signal transducers and activators of transcription (STAT) 1 and STAT3, activation of nuclear factor-κB and expression of iNOS mRNA. Notably, administration of CT-1 (20 μg/kg iv) immediately prior to LPS significantly inhibited all of these LPS-induced changes. To determine whether SOCS1 expression in cardiomyocytes is sufficient to inhibit LPS- and cytokine-induced expression of iNOS mRNA, the effects of forced expression of SOCS1 in cultured neonatal cardiomyocytes were investigated using an adenovirus-mediated transfection system. Forced expression of SOCS1 significantly inhibited iNOS transcription induced by LPS, tumor necrosis factor-α or interferon-γ. Conclusions CT-1-mediated expression of SOCS1 in cardiomyocytes may be a useful target for preventing sepsis-induced myocardial depression. (Circ J 2005; 69: 1412 - 1417)