Suppression of VSMC Activation and Mechanisms of Vascular Protection by IL-19

IL-19抑制VSMC激活及血管保护机制

基本信息

批准号：
7802092
负责人：
MICHAEL V AUTIERI
金额：
$ 37.5万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7802092
关键词：
Address Affinity Angioplasty Anti-Inflammatory Agents Anti-inflammatory Arteries Atherosclerosis Attention Balloon Angioplasty Binding Proteins Blood Vessels Cardiovascular Diseases Carotid Arteries Cells Coronary artery Cyclins Cytokine Inducible SH2-Containing Protein Cytoprotection Data Development Dominant-Negative Mutation Down-Regulation Economic Burden Event FOS gene Family Functional disorder Gene Expression Gene Transfer Genes Goals Human Hyperplasia IL8 gene Immune Inflammation Inflammatory Injury Intercellular adhesion molecule 1 Interleukin-10 Knockout Mice MAP Kinase Gene Mediating Medical Economics Messenger RNA Mitogen-Activated Protein Kinases Modality Nature PTGS2 gene Pathway interactions Play Post-Translational Protein Processing Process Proteins Rattus Reporting Role STAT3 gene Signal Pathway Signal Transduction Signal Transduction Pathway Smooth Muscle Myocytes Societies Testing Therapeutic Transgenic Mice Transplantation United States Vascular Diseases attenuation autocrine cytokine design in vivo injured interleukin-19 knock-down member mortality novel protective effect public health relevance response response to injury small hairpin RNA vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): The development of multiple vascular diseases ranging from atherosclerosis to transplant vasculopathy are inflammatory in nature. Although much is known about the deleterious effects of pro-inflammatory cytokines on vascular smooth muscle cells (VSMC) pathophysiology, we know very little about the direct protective effects of anti-inflammatory cytokines on VSMC. Our overall hypothesis is that IL -19 plays a protective role in the vascular response to injury by direct inhibitory effects on VSMC activation. IL-19 is a recently described member of the IL -10 family of anti-inflammatory cytokines. IL-19 expression is ascribed to be restricted to hematopoetic and inflammatory cells, where it has an anti-inflammatory effect. Nothing has been reported on the mechanism(s) of IL-19 effects, either in immune or vascular cells. We have found that; IL-19 is not expressed in quiescent VSMC or normal arteries, but is induced in VSMC by inflammatory cytokines and in arteries by injury; IL -19 is anti-proliferative for cultured, human coronary artery VSMC, induces activation of STAT-3; inhibits activation of signal transduction MAPK and expression of proliferative and inflammatory genes. IL -19 induces expression of the suppressor of cytokine signaling 5 (SOCS5), but inhibits expression and translocation of HuR, a stability factor which regulates decay of inflammatory and proliferative gene mRNA. IL-19 adenoviral gene transfer significantly reduces neointimal formation and VSMC proliferation in balloon angioplasty-injured rat carotid arteries. The overall goals of this application are designed to characterize the mechanism of IL -19 suppressive effects on VSMC and development of progression of intimal hyperplasia in response to vascular injury. We will test the hypothesis that STAT3 activation, SOCS5 expression, and HuR down-regulation are critical events in IL -19 mediated VSMC protection. We will test the hypothesis that IL-19 has protective effects on VSMC by decreasing expression of proliferative and inflammatory genes, and will define the mechanism(s) of these effects. We will test the hypothesis that IL -19 anti-restenotic effects in vivo are due at least in part by attenuation of inflammatory and proliferative gene expression, mediated by expression of SOCS5 and down regulation of HuR. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the number one cause of mortality in the United States and places an enormous medical and economic burden on our society. This application will address the novel concept of direct beneficial effects of anti- inflammatory cytokines on vascular pathophysiology.

描述（由申请人提供）：从动脉粥样硬化到移植血管病的多种血管疾病的发展本质上是炎症性的。尽管人们对促炎细胞因子对血管平滑肌细胞 (VSMC) 病理生理学的有害影响了解甚多，但我们对抗炎细胞因子对 VSMC 的直接保护作用知之甚少。我们的总体假设是，IL -19 通过直接抑制 VSMC 激活，在血管对损伤的反应中发挥保护作用。 IL-19 是最近描述的抗炎细胞因子 IL -10 家族的成员。 IL-19 的表达被认为仅限于造血细胞和炎症细胞，具有抗炎作用。关于 IL-19 在免疫细胞或血管细胞中的作用机制尚未有任何报道。我们发现； IL-19 在静止的 VSMC 或正常动脉中不表达，但在 VSMC 中被炎性细胞因子诱导表达，在动脉中被损伤诱导表达； IL -19 对培养的人冠状动脉 VSMC 具有抗增殖作用，可诱导 STAT-3 激活；抑制信号转导 MAPK 的激活以及增殖和炎症基因的表达。 IL -19 诱导细胞因子信号传导抑制因子 5 (SOCS5) 的表达，但抑制 HuR 的表达和易位，HuR 是调节炎症和增殖基因 mRNA 衰减的稳定因子。 IL-19腺病毒基因转移显着减少球囊血管成形术损伤的大鼠颈动脉中的新内膜形成和VSMC增殖。本申请的总体目标旨在表征 IL -19 对 VSMC 抑制作用的机制以及响应血管损伤的内膜增生进展的发展。我们将检验以下假设：STAT3 激活、SOCS5 表达和 HuR 下调是 IL -19 介导的 VSMC 保护中的关键事件。我们将检验 IL-19 通过减少增殖和炎症基因的表达对 VSMC 具有保护作用的假设，并定义这些作用的机制。我们将检验以下假设：IL -19 体内抗再狭窄作用至少部分是由于 SOCS5 表达和 HuR 下调介导的炎症和增殖基因表达减弱所致。公共卫生相关性：心血管疾病是美国第一大死因，给我们的社会带来巨大的医疗和经济负担。该应用将提出抗炎细胞因子对血管病理生理学的直接有益作用的新概念。