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

CIS（细胞因子诱导型SH 2蛋白）、SOCS（细胞因子信号传导抑制剂）或SSI（STAT诱导的STAT抑制剂）蛋白是通过Janus激酶（JAK）-信号转导子和转录激活子（STAT）途径的细胞因子信号传导的丝氨酸诱导型负调节因子家族。鉴于JAK-STAT通路在心血管系统中起关键作用的证据，本研究的主要目的是评估CIS家族对用心肌营养素-1（CT-1）（一种白细胞介素-6家族细胞因子）处理的大鼠心血管系统中JAK-STAT信号传导的影响。静脉注射20μg/kg体重的CT- 1诱导包括心脏和肺在内的各种组织中的STAT 3活化的短暂显著增加，以及随后CIS家族的两个成员JAK结合蛋白（JAB）/SOCS-1/SSI-1和CIS 3/SOCS-3/SSI-3在相同组织中的上调。在第二次注射CT-1之前60分钟用相同剂量的CT-1预处理显著减弱了由第二次注射CT-1诱导的STAT 3活化。在大鼠预处理CT-1诱导的iNOS mRNA或低血压，随后CT-1注射没有观察到。此外，我们证明，预处理CT-1衰减左心室功能诱导的非致命剂量的LPS和LPS诱导的心功能不全是钝化在小鼠过表达JAB/SOCS-1的心脏特异性。

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.