SOCS1/JAB likely mediates the protective effect of cardiotrophin-1 against lipopolysaccharide-induced left ventricular dysfunction in vivo.
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.


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-kappaB and expression of iNOS mRNA. Notably, administration of CT-1 (20 microg/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-alpha or interferon-gamma.


CONCLUSIONS
CT-1-mediated expression of SOCS1 in cardiomyocytes may be a useful target for preventing sepsis-induced myocardial depression.
Tanimoto
Keiji
K
Department of Medicine and Clinical Science, Japan.
Saito
Yoshihiko
Y
Hamanaka
Ichiro
I
Kuwahara
Koichiro
K
Harada
Masaki
M
Takahashi
Nobuki
N
Kawakami
Rika
R
Nakagawa
Yasuaki
Y
Nakanishi
Michio
M
Adachi
Yuichiro
Y
Shirakami
Gotaro
G
Fukuda
Kazuhiko
K
Yoshimura
Akihiko
A
Nakao
Kazuwa
K
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000008:administration & dosage*; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*
D016207:Cytokines; D008070:Lipopolysaccharides; C491589:Socs1 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C092073:cardiotrophin 1