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

基于细胞因子抵抗的充血性心力衰竭和缺血再灌注损伤的治疗新方法

基本信息

批准号：
13470144
负责人：
SAITO Yoshihiko
金额：
$ 9.22万
依托单位：
NARA MEDICAL UNIVERSITY (2002)Kyoto University (2001)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470144/
关键词：
SOCS1 SOCS3 Cytokine Resistance CT-1 NF-_kB SOCSI サイトカイン SOCS カルディオトロピン STAT LPS

项目摘要

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.

细胞因子诱导的SH2蛋白、细胞因子信号转导抑制因子或STAT诱导的STAT抑制因子蛋白是一类细胞因子诱导的负调控因子，它们通过JAK信号转导和转录激活因子(STAT)途径调节细胞因子信号。有证据表明JAK-STAT通路在心血管系统中起着关键作用，本研究的主要目的是在心肌营养素-1(CT-1)(一种白介素6细胞因子家族)治疗的大鼠中，评估CIS家族对心血管系统JAK-STAT信号的影响。静脉注射20μg/kg体重的CT-1可引起心脏和肺等多种组织中STAT3活性的一过性升高，随后同一组织中的JAK结合蛋白(Jab)/SoCS-1/SSi-1和Cis3/SoCS-3/SSi-3表达上调。在注射前60分钟给予相同剂量的CT-1可明显减弱再次注射CT-1对STAT3的激活作用。在CT-1预处理的大鼠中，没有观察到诱导型一氧化氮合酶mRNA的诱导或随后注射CT-1的降压。此外，我们证明，CT-1预处理可以减弱非致死剂量的内毒素和内毒素诱导的心功能障碍所致的左心功能，在心脏中过度表达JAB/SOCS-1的小鼠是钝化的。