Negative Impact of Alcohol on Cardiovascular Neurobiology

描述(申请人提供)：酒精引起独特的心血管反应，这不仅取决于脑干内的神经元底物，还取决于这些神经元的遗传状态。本研究旨在阐明乙醇对自发性高血压大鼠(SHR)模型脑干中控制血压和心脏反射的特殊神经元的不同作用所涉及的分子机制。我们最近的有趣发现表明，乙醇在延髓腹外侧部(RVLM)和孤束核(NTS)引起的位置依赖性神经化学(去甲肾上腺素，NE)和IEG基因/蛋白表达(c-Jun/c-Jun)反应决定了它对高血压和正常血压大鼠血压和压力感受性反射反应的不同影响。鉴于SHR心血管神经生物学和神经元对乙醇敏感性的改变，我们推测血红素加氧酶(HO)衍生的一氧化碳(CO)构成了中枢神经系统的一种新的分子机制！乙醇对心血管的影响。为了验证这一假设，我们提出了三个目标下的一系列综合的分子研究。目的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。目的2阐明乙醇对SHR和WKY大鼠脑干神经元HO及其调控蛋白小窝蛋白-1和钙调蛋白结合的影响。目的3研究HO-CO-MAPK通路在乙醇诱导的心血管反应中的作用。由于过氧化氢酶(大脑中代谢乙醇的主要酶)的活性在SHR中发生了变化，因此将研究乙醛对乙醇作用的潜在贡献。该提案采用了精心设计的实验方法，包括已建立的模型系统、适当的控制以及药理学和siRNA干预：(I)建立HO来源的CO抑制与乙醇的交感兴奋(升压)和压力感受性反射抑制效应之间的因果关系，以及(Ii)确定乙醇的位置和应变依赖的神经化学和心血管效应所涉及的分子机制。这项拟议的研究主要关注于探索乙醇对心血管神经生物学不利影响的分子机制，解决了一个重要的生物医学问题，并有望获得临床相关信息。

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.