Ethanol mediated endothelial injury and dysfunction

乙醇介导的内皮损伤和功能障碍

• 批准号: 7476694
• 负责人: Raj Kishore
• 金额: $ 12.98万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7476694
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; angiogenesis; apoptosis; behavioral /social science research tag; biological models; biological signal transduction; cellular pathology; ethanol; genetically modified animals; ischemia; laboratory mouse; pharmacokinetics; protein structure function; stem cells; substance abuse related behavior; tumor necrosis factor alpha; vascular endothelium

DESCRIPTION (provided by applicant): Chronic alcoholism remains one of the major risk factors in the pathogenesis of cardiovascular diseases. Dose related bimodal effects of alcohol on cardiovascular system may reflect contrasting influences of light versus heavy alcohol consumption on the vascular endothelium. TNF expressed at the sites of arterial injury following balloon angioplasty suppresses endothelial cell (EC) proliferation and contributes to the development of restenosis. We have shown that in vitro exposure of EC to ethanol not only upregulates TNF transcription and expression but also synergistically exacerbates inhibitory effects of TNF on ECs. Our preliminary data indicates that chronic ethanol feeding in mice delays endothelial recovery and enhances intimal hyperplasia in denuded carotid arteries. At least, part of ethanol responses are mediated via TNF since TNFRI null mice are protected from ethanol-mediated effects on vascular endothelium. Our preliminary data also shows that ethanol feeding impairs neo-vascularization in the surgically induced ischemic hind limbs. Endothelial progenitor cells (EPC) have repeatedly been shown to mediate the processes of reendothelialization and neo-vascularization. Interestingly, our preliminary data indicates that kinetics and function of circulating EPCs from mice fed on alcohol is severely compromised. Considering the therapeutic potential for exploiting bone marrow derived progenitors/stem cells for cardiac repair as evident by recent surge in the number of high impact studies reported in the literature, it becomes additionally imperative to assess the effect of chronic alcohol either alone or synergistically with TNF, on the behavior and function of these progenitor cells, in vivo, especially in terms of their participation in the repair of ischemic tissue via neo-vascularization. Its our hypothesis that chronic ethanol impairs the function of EPCs and thereby negatively affect vasculogenesis and that part of ethanol effect on EPCs are mediated via the augmentation of TNF receptor l-mediated augmentation in apoptotic signaling. Using mice model of chronic ethanol feeding followed by surgically induce hind limb ischemia, we propose to verify these hypotheses under following specific aims: Specific Aim 1: Determine the effect of chronic alcohol on post-injury neovascularization and EPC kinetics and function in a mouse model of hind limb ischemia. Specific aim 2: Evaluate the contribution of TNFRI in alcohol-mediated EPC dysfunction.

描述（由申请人提供）：慢性酒精中毒仍然是心血管疾病发病机制的主要危险因素之一。 酒精对心血管系统的剂量相关双峰效应可能反映了少量饮酒与大量饮酒对血管内皮的对比影响。球囊血管成形术后动脉损伤部位表达的 TNF 可抑制内皮细胞 (EC) 增殖并促进再狭窄的发生。我们已经证明，EC 体外暴露于乙醇不仅上调 TNF 转录和表达，而且协同加剧 TNF 对 EC 的抑制作用。我们的初步数据表明，小鼠长期喂食乙醇会延迟内皮恢复并增强裸露颈动脉的内膜增生。至少，部分乙醇反应是通过 TNF 介导的，因为 TNFRI 缺失的小鼠可以免受乙醇介导的血管内皮效应。我们的初步 数据还显示，乙醇喂养会损害手术引起的缺血后肢的新血管形成。内皮祖细胞 (EPC) 已多次被证明可以介导再内皮化和新血管形成的过程。有趣的是，我们的初步数据表明，喂食酒精的小鼠循环 EPC 的动力学和功能受到严重损害。考虑到利用骨髓来源的祖细胞/干细胞进行心脏修复的治疗潜力，正如最近文献中报告的高影响研究数量激增所证明的那样，评估单独或与 TNF 协同作用的慢性酒精的作用变得尤为重要，这些祖细胞在体内的行为和功能，特别是它们通过新血管形成参与缺血组织的修复。我们的假设是，长期乙醇会损害 EPC 的功能，从而对血管发生产生负面影响，并且乙醇对 EPC 的部分影响是通过增强 TNF 受体 I 介导的细胞凋亡信号传导来介导的。使用慢性乙醇喂养的小鼠模型，然后通过手术诱导后肢缺血，我们建议在以下具体目标下验证这些假设： 具体目标 1：确定慢性酒精对小鼠模型中损伤后新生血管形成以及 EPC 动力学和功能的影响后肢缺血。具体目标 2：评估 TNFRI 在酒精介导的 EPC 功能障碍中的作用。