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

Keiji Tanimoto, Yoshihiko Saito, Ichiro Hamanaka, Koichiro Kuwahara, Masaki Harada, Nobuki Takahashi, Rika Kawakami, Yasuaki Nakagawa, Michio Nakanishi, Yuichiro Adachi, Gotaro Shirakami, Kazuhiko Fukuda, Akihiko Yoshimura, Kazuwa Nakao

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13 Citations (Scopus)

Abstract

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- B and expression of iNOS mRNA. Notably, administration of CT-1 (20 g /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- or interferon-. Conclusions: CT-1-mediated expression of SOCS1 in cardiomyocytes may be a useful target for preventing sepsis-induced myocardial depression.

Original languageEnglish
Pages (from-to)1412-1417
Number of pages6
JournalCirculation Journal
Volume69
Issue number11
DOIs
Publication statusPublished - 2005 Nov 14
Externally publishedYes

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Keywords

  • Cardiotrophin-1
  • Lipopolysaccharide
  • SOCS1/JAB
  • Sepsis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Tanimoto, K., Saito, Y., Hamanaka, I., Kuwahara, K., Harada, M., Takahashi, N., Kawakami, R., Nakagawa, Y., Nakanishi, M., Adachi, Y., Shirakami, G., Fukuda, K., Yoshimura, A., & Nakao, K. (2005). SOCS1/JAB likely mediates the protective effect of cardiotrophin-1 against lipopolysaccharide-induced left ventricular dysfunction in vivo. Circulation Journal, 69(11), 1412-1417. https://doi.org/10.1253/circj.69.1412