Negative Impact of Alcohol on Cardiovascular Neurobiology

酒精对心血管神经生物学的负面影响

• 批准号: 8135112
• 负责人: ABDEL A ABDEL-RAHMAN
• 金额: $ 5万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-05 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135112
• 关键词: Acetaldehyde; Acute; Address; Adopted; Adverse effects; Alcohol consumption; Alcohols; Animal Model; Area; Baroreflex; Binding; Biological Models; Biology; Blood Pressure; Brain; Brain Stem; Calmodulin; Carbon Monoxide; Cardiac; Cardiovascular system; Catabolism; Caveolins; Conscious; Dose; Enzymes; Essential Hypertension; Ethanol; Experimental Designs; Experimental Models; FOS gene; Functional disorder; Gene Proteins; Genetic; Health; Heme; Human; Hypertension; Immunoprecipitation; Inbred SHR Rats; Inbred WKY Rats; Intervention; JUN gene; Knowledge; MAP Kinase Gene; MAPK14 gene; MAPK8 gene; Mediating; Metabolic; Modeling; Molecular; Molecular Probes; Neurobiology; Neurons; Norepinephrine; Nucleus solitarius; Oxygenases; Pathway interactions; Phosphorylation; Proteins; Rattus; Reflex action; Research; Research Personnel; Role; Second Messenger Systems; Series; Signal Transduction; Site; Small Interfering RNA; Spatial Distribution; Testing; Western Blotting; alcohol effect; alcohol sensitivity; blood pressure regulation; catalase; caveolin 1; clinically relevant; enzyme activity; genetic regulatory protein; heme oxygenase-1; interdisciplinary approach; neurochemistry; normotensive; novel; programs; protein expression; response; second messenger

DESCRIPTION (provided by applicant): Alcohol elicits unique cardiovascular responses, which are not only dependent on the neuronal substrates within the brainstem but also on the genetic state of these neurons. The objective of this proposal is to elucidate the molecular mechanisms implicated in the differential effect of ethanol on specialized neurons in the brainstem that control blood pressure and cardiac reflexes in a model of essential hypertension, the spontaneously hypertensive rat (SHR). Our recent intriguing findings showed that site dependent neurochemical (norepinephrine, NE) and IEG gene/protein expression (c-jun/c-Jun) responses elicited by ethanol in the ventrolateral medulla (RVLM) and nucleus tractus solitarius (NTS) determine its divergent effects on blood pressure and baroreflex responses in hypertensive and normotensive rats. Given the altered cardiovascular neurobiology and neuronal sensitivity to ethanol in SHRs, we hypothesize that heme oxygenase (HO) derived carbon monoxide (CO) constitutes a novel molecular mechanism for the centra! cardiovascular effects of ethanol. To test this hypothesis, we propose a series of integrative, and molecular studies under three aims. Aim 1 establishes brainstem HO-CO pathway as a molecular mechanism for the divergent cardiovascular actions of ethanol in SHRs and WKY rats. Aim 2 will elucidate the effect of ethanol on the association of HO with its regulatory proteins caveolin-1 and calmodulin in brainstem neurons of SHRs and WKY rats. Aim 3 characterizes the role of HO-CO-MAPK pathway in ethanol-mediated cardiovascular responses. Since catalase activity (the major enzyme that metabolizes ethanol in the brain) is altered in SHRs, the potential contribution of acetaldehyde to ethanol actions will be investigated. The proposal adopts a well designed experimental approach that incorporates an established model system, appropriate controls and pharmacological and siRNA interventions to: (i) establish a causal relationship between inhibition of HO-derived CO and the sympathoexcitatory (pressor) and baroreflex depressant effects of ethanol, and (ii) identify the molecular mechanisms implicated in the site- and strain-dependent neurochemical and cardiovascular effects of ethanol. The proposed research whose primary focus is to probe the molecular mechanisms implicated in the adverse ethanol effects on cardiovascular neurobiology, addresses a significant biomedical problem and is expected to yield clinically relevant information.

描述（由申请人提供）：酒精会引起独特的心血管反应，该反应不仅取决于脑干内的神经元基质，还取决于这些神经元的遗传状态。该提案的目的是阐明乙醇对原发性高血压模型（自发性高血压大鼠（SHR））脑干中控制血压和心脏反射的特殊神经元的不同影响所涉及的分子机制。我们最近有趣的发现表明，乙醇在腹外侧髓质（RVLM）和孤束核（NTS）中引起的位点依赖性神经化学物质（去甲肾上腺素，NE）和IEG基因/蛋白质表达（c-jun/c-Jun）反应决定了其分歧对高血压和正常血压大鼠的血压和压力反射反应的影响。鉴于 SHR 中心血管神经生物学和神经元对乙醇敏感性的改变，我们假设血红素加氧酶 (HO) 衍生的一氧化碳 (CO) 构成了该中心的一种新的分子机制！乙醇对心血管的影响。为了检验这一假设，我们在三个目标下提出了一系列综合性分子研究。目标 1 建立脑干 HO-CO 通路作为乙醇对 SHR 和 WKY 大鼠不同心血管作用的分子机制。目标 2 将阐明乙醇对 SHR 和 WKY 大鼠脑干神经元中 H2O 与其调节蛋白 Caveolin-1 和钙调蛋白的关联的影响。目标 3 描述了 HO-CO-MAPK 通路在乙醇介导的心血管反应中的作用。由于过氧化氢酶活性（大脑中代谢乙醇的主要酶）在 SHR 中发生改变，因此将研究乙醛对乙醇作用的潜在贡献。该提案采用精心设计的实验方法，结合了已建立的模型系统、适当的对照以及药理学和 siRNA 干预措施，以：（i）建立 H2O2 衍生 CO 的抑制与乙醇的交感兴奋（升压）和压力感受反射抑制作用之间的因果关系，和（ii）确定与乙醇的位点和应变依赖性神经化学和心血管作用有关的分子机制。拟议的研究的主要重点是探讨乙醇对心血管神经生物学的不良影响所涉及的分子机制，解决了一个重要的生物医学问题，并有望产生临床相关信息。