Human Resistance Artery Functional Changes with Alcohol Use

饮酒后人体阻力动脉功能的变化

• 批准号: 10372624
• 负责人: JEROME W BRESLIN
• 金额: $ 19.65万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372624
• 关键词: Acceleration; Address; Adrenergic Agents; Adrenergic Receptor; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Antihypertensive Agents; Arteries; Biochemical; Biology; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chronic; Clinic; Consumption; Data; Development; Endocrine; Endothelial Cells; Endothelium; Evaluation; Future; Genetic Transcription; Health; Heavy Drinking; Human; Human Characteristics; Hypertension; Image; Impact evaluation; Impairment; Intention; Knowledge; Ligands; Light; Mediating; Mesenteric Arteries; Mesentery; Mind; Mission; Modeling; Molecular; Molecular Chaperones; Muscle Contraction; Myography; Organ Donor; Outcome; Pathway interactions; Persons; Pharmaceutical Preparations; Physiological; Population; Pre-Clinical Model; Productivity; Proteins; Proteome; Proteomics; Public Health; Publishing; Receptor Signaling; Recording of previous events; Research; Resistance; Risk Factors; Rodent; Rodent Model; Role; Safety; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Solid; Testing; Therapeutic; Tissue Model; Tissues; Translations; United States National Institutes of Health; Untranslated RNA; Vascular Endothelium; Vascular Smooth Muscle; Vasodilation; Work; Workplace; alcohol exposure; alcohol measurement; alcohol use disorder; antagonist; base; burden of illness; chronic alcohol ingestion; clinically relevant; constriction; cost; design; drinking behavior; human tissue; innovation; insight; new therapeutic target; novel; problem drinker; receptor; receptor expression; relating to nervous system; response; sex; sigma receptors; sigma-1 receptor; translational impact; trend; vascular inflammation

Hypertension is the single most important risk factor for global burden of disease, and significant percentages of hypertension are attributed to alcohol consumption. While much focus has been placed on how alcohol alters the neural, endocrine, and intrinsic cardiovascular mechanisms controlling blood pressure in rodents, there is a significant gap in knowledge of how human resistance arteries are altered by chronic alcohol consumption, both functionally and in terms of their underlying molecular composition. Interestingly, the chaperone proteins known as sigma receptors-1 and -2 have been shown: 1) to be modulators of alcohol drinking behavior in rodents, and 2) to also be abundantly expressed in vascular tissues, with the ability to alter smooth muscle contraction. Thus, it is possible that drugs that modulate sigma receptor activity and reduce alcohol intake in preclinical models may also provide the added benefit of accelerating the reversal of alcohol- induced hypertension. On the other hand, because there is currently a significant gap in knowledge about the specific role of sigma receptors in vascular functions, it is also possible that the advancement of novel therapeutics targeting sigma receptors with the intention of reducing alcohol intake may in fact exacerbate hypertension in alcoholics and limit the usefulness of this promising approach. With this in mind, the overall objective of the current application is to determine the putative role of sigma receptors in alcohol-induced hypertension. The central hypothesis is that chronic alcohol use promotes sigma-receptor-mediated amplification of adrenergic receptor signaling in resistance arteries. The rationale for the proposed research is that understanding of how chronic alcohol use impacts sigma receptor expression, signaling, and function in resistance arteries would permit informed decisions about the safety of future therapeutic strategies targeting sigma receptors to treat alcohol addiction. Guided by robust preliminary data, the central hypothesis will be tested with two specific aims. Aim 1 is to determine the differential sigma receptor signaling in vascular smooth muscle underlying changes in human resistance artery reactivity that accompany chronic alcohol use. Aim 2 is investigate the alcohol-induced changes in vascular endothelial sigma receptor signaling. The experimental endpoints will be functional reactivity of human mesenteric arteries obtained from organ donors, in the absence and presence of sigma receptor modulators, correlated the de-identified donor histories of alcohol use and other factors including sex and hypertension, plus proteomic trends and changes in noncoding RNAs that occur in resistance arteries in relation to levels of alcohol use. The contribution of the proposed research will be significant because it will provide the first direct evaluation of the impact of chronic alcohol use on the intrinsic activity and proteomic composition of human resistance arteries. The proposed research is innovative because it represents a substantial departure from the status quo of using rodents to study how chronic alcohol use impacts vascular functions, while addressing the novel role of sigma receptors in vascular tissue.

高血压是全球疾病负担的最重要的危险因素，并且很大 高血压归因于饮酒。虽然将重点放在酒精的方式上 改变控制啮齿动物血压的神经，内分泌和内在的心血管机制， 关于人类抵抗动脉如何通过慢性酒精改变的知识存在很大的差距 在功能和基本分子组成方面的消耗。有趣的是， 伴侣蛋白称为Sigma受体-1和-2：1）是酒精的调节剂 啮齿动物中的饮酒行为，2）在血管组织中也充分表达 平滑肌收缩。因此，有可能调节Sigma受体活性并降低的药物 临床前模型中的酒精摄入量还可能带来加速酒精逆转的额外好处。 诱发高血压。另一方面，因为目前有关 Sigma受体在血管功能中的特定作用，新型的发展也可能 靶向西格玛受体以减少酒精摄入量的治疗剂实际上可能加剧 酗酒者中的高血压并限制了这种有前途的方法的有用性。考虑到这一点，总体 当前应用的目的是确定Sigma受体在酒精诱导的推定作用 高血压。中心假设是慢性饮酒促进了Sigma受体介导的 耐药性动脉中肾上腺素能受体信号传导的扩增。拟议研究的理由是 对慢性酒精使用如何影响Sigma受体表达，信号传导和功能的理解 抵抗动脉将允许有关未来治疗策略的安全性的明智决定 Sigma受体治疗酒精成瘾。在强大的初步数据的指导下，中心假设将是 以两个特定的目的进行测试。 AIM 1是确定血管光滑中的差异Sigma受体信号传导 慢性酒精使用伴随着人类抗性动脉反应性的肌肉变化。 AIM 2是 研究酒精诱导的血管内皮sigma受体信号传导的变化。实验 终点将是从器官捐献者获得的人肠系膜动脉的功能反应性，而在不存在的情况下 以及Sigma受体调节剂的存在，将饮酒和使用的供体历史与 其他因素，包括性别和高血压，以及蛋白质组学趋势以及​​非编码RNA的变化， 与酒精使用水平有关的电阻动脉发生。拟议的研究的贡献将 要重要的是因为它将首先直接评估慢性饮酒对 人类抗性动脉的内在活性和蛋白质组学组成。拟议的研究是创新的 因为它代表了使用啮齿动物研究慢性酒精的现状很大的现状 使用会影响血管功能，同时解决Sigma受体在血管组织中的新作用。