New Therapeutic Approach for Congestive Heart Failure and Ischemia - reperfusion Injury Based on Cytokine Resistance

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CIS (cytokine inducible SH2 protein), SOCS (suppressor of cytokine signaling) or SSI (STAT-induced STAT inhibitor) proteins are a family of cytokine-inducible negative regulators of cytokine signaling via Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. Given the evidence that JAK-STAT pathway plays a critical role in the cardiovascular system, the primary objective of this study is to assess the effects of CIS family on JAK-STAT signaling in the cardiovascular system in rats treated with cardiotrophin-1 (CT-1), an interleukin-6 family of cytokine. Intravenous injection of 20μg/kg body wt of CT- 1 induced transient, markedly increase in STAT3 activation in various tissues including heart and lung, and subsequent up-regulation of two members of CIS family, JAK binding protein (JAB)/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 in same tissues. Pretreatment with the same dose of CT-1 60 minutes before significantly attenuated the STAT3 activation induced by a second injection of CT-1. In rats pretreated with CT-1 either the induction of iNOS mRNA or hypotension by subsequent CT-1 injection was not observed. Furthermore, we demonstrate that pretreatment with CT-1 attenuated left ventricular function induced by non-fatal dose of LPS and LPS-induced cardiac dysfunction was blunted in mice over-expressing JAB/SOCS-1 specifically in heart.