Ethanol Prevents Microvascular Dysfunction

乙醇预防微血管功能障碍

• 批准号: 7630624
• 负责人: RONALD JOHN KORTHUIS
• 金额: $ 32.38万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7630624
• 关键词: 5' -AMP-activated protein kinase; Acids; Address; Adhesions; Adhesives; Alcohol consumption; Alcoholic Beverages; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Beer; Blood Platelets; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cell Adhesion Molecules; Chloride Ion; Chlorides; Consumption; Cystic Fibrosis Transmembrane Conductance Regulator; Cytochrome P450; Development; Dose; Elements; Endothelial Cells; Enzymes; Epidemiologic Studies; Ethanol; Event; Exhibits; Functional disorder; Heart; Hour; Incidence; Individual; Ischemia; Leukocyte Rolling; Leukocytes; Link; Lipids; Mediator of activation protein; Metabolic; Microcirculation; Microscopic; Mus; Mutant Strains Mice; Myocardial Infarction; Nitric Oxide; P-Selectin; Peptide antibodies; Phase; Phenotype; Plasma; Play; Property; Protein Isoforms; Protein Kinase C; Reaction; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Role; Secondary to; Signal Transduction; Surface; Tissues; Wine; Work; alcohol effect; alcohol exposure; calcium-dependent protein kinase; drinking; human NOS3 protein; improved; novel; postcapillary venule; preconditioning; prevent; programs; protein expression

DESCRIPTION (provided by applicant): Ethanol consumption at low to moderate levels protects the heart and vasculature from the deleterious effects of ischemia and reperfusion (I/R). Our recent work indicates that antecedent ethanol ingestion provokes the development of an anti-inflammatory phenotype in postcapillary venules such that these microvessels fail to support leukocyte/endothelial cell adhesive interactions during I/R. Surprisingly, AMP-activated kinase (AMPK) plays a necessary role in initiating this adaptive transformation to a protected phenotype in postcapillary venules. However, it is not clear how this enzyme, best known for its role as a metabolic master switch, is involved in transducing signals elicited by ethanol to effect the acquisition of tolerance to I/R in the microcirculation. Our overall hypothesis is that ethanol-induced, AMPK-dependent eNOS activation serves as an important initiating factor to trigger a cascade of signaling events that ultimately act to promote the expression of cytochrome P450 epoxygenases (CYP), which serve as an important effector of the beneficial microvascular actions of ethanol by catalyzing the formation of reaction products which exhibit powerful anti-adhesive and antioxidant properties. To address this postulate, we propose to determine whether: (1) ethanol-induced AMPK activation initiates the development of an anti-inflammatory phenotype by stimulating the formation of eNOS-derived NO; (2) NO-induced release of calcitonin gene-related peptide (CGRP) plays an essential role in the acquisition of tolerance to ischemia that is evoked by antecedent ethanol consumption; (3) the cystic fibrosis transmembrane regulator (CFTR) serves as an obligatory downstream signaling element that participates in inaugurating the development of the protected phenotype precipitated by ethanol-induced AMPK activation; and (4) ethanol-induced, AMPK-triggered increases in CYP activity during I/R prevents postischemic leukocyte adhesion in postcapillary venules by abrogating P-selectin expression. Intravital microscopic approaches will be used to quantify leukocyte rolling and adhesion in wild-type control mice and in mutant mice lacking AMPK, eNOS, CGRP, or CFTR. The influence of ethanol on l/R-induced adhesion molecule expression, AMPK and eNOS activity, CGRP release, and CYP protein expression and activity will also be investigated. Collectively, these aims address novel mechanisms whereby antecedent ethanol ingestion induces the development of an anti-inflammatory phenotype in postcapillary venules. This work will identify new links between ethanol-induced, AMPK-dependent, eNOS-derived NO formation as essential triggering elements, CGRP release and CFTR function as obligatory downstream mediators, and increased CYP activity as a major effector in the acquisition of tolerance to I/R by antecedent ethanol ingestion.

描述（由申请人提供）：低至中等水平的乙醇消耗可保护心脏和血管系统免受缺血和再灌注（I/R）的有害影响。我们最近的工作表明，先前的乙醇摄入会引起毛细血管后微静脉中抗炎表型的发展，使得这些微血管在I/R期间无法支持白细胞/内皮细胞粘附相互作用。令人惊讶的是，AMP激活激酶（AMPK）在启动这种适应性转化为受保护的表型在毛细血管后微静脉中起着必要的作用。然而，目前尚不清楚这种酶，最为人所知的作用作为一个代谢的主开关，是如何参与由乙醇引起的信号转导，以影响获得耐受性的微循环中的I/R。我们的总体假设是，乙醇诱导的AMPK依赖性eNOS活化作为一个重要的起始因子，触发一系列信号传导事件，最终促进细胞色素P450环氧合酶（CYP 450 epoxygenases，CYP 450 epoxygenases）的表达，其通过催化反应产物的形成，表现出强大的抗粘附和抗氧化特性，作为乙醇有益微血管作用的重要效应物。为了解决这一假设，我们打算确定：（1）乙醇诱导的AMPK激活是否通过刺激eNOS衍生的NO的形成启动抗炎表型的发展;（2）NO诱导的降钙素基因相关肽（CGRP）的释放在获得对缺血的耐受中起重要作用，这是由先前的乙醇消耗引起的;（3）囊性纤维化跨膜调节因子（CFTR）作为一种必需的下游信号元件，参与启动由乙醇诱导的AMPK活化沉淀的受保护表型的发展;（4）乙醇诱导的AMPK触发的I/R过程中血小板活性的增加通过消除P-选择素的表达来防止缺血后毛细血管后微静脉中白细胞的粘附。将使用活体显微镜方法定量野生型对照小鼠和缺乏AMPK、eNOS、CGRP或CFTR的突变小鼠中的白细胞滚动和粘附。还将研究乙醇对I/R诱导的粘附分子表达、AMPK和eNOS活性、CGRP释放以及CGRP蛋白表达和活性的影响。总的来说，这些目标解决了新的机制，即先行乙醇摄入诱导发展的抗炎表型在毛细血管后小静脉。这项工作将确定乙醇诱导的，AMPK依赖的，eNOS衍生的NO形成作为必要的触发元件，CGRP释放和CFTR功能作为强制性下游介质，并增加作为一个主要效应器的活性增加的β-内酰胺酶在收购耐受性的I/R由先行乙醇摄入之间的新的联系。