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: 10589888
• 负责人: JEROME W BRESLIN
• 金额: $ 17.75万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589888
• 关键词: Acceleration; Address; Adrenergic Agents; Adrenergic Receptor; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Antihypertensive Agents; Arteries; Biochemical; Biology; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chronic; Clinic; Consumption; Data; Development; Drug Modulation; 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; 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; United States National Institutes of Health; Untranslated RNA; Vascular Endothelium; Vascular Smooth Muscle; Vasodilation; Work; Workplace; alcohol exposure; alcohol measurement; alcohol use disorder; antagonist; blood pressure control; burden of illness; chronic alcohol ingestion; clinically relevant; constriction; cost; design; drinking behavior; human tissue; innovation; insight; neural; new therapeutic target; novel; problem drinker; receptor; receptor expression; response; sex; sigma receptors; sigma-1 receptor; translational impact; translational therapeutics; 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.

高血压是造成全球疾病负担的最重要的单一风险因素， 高血压的主要原因是饮酒。虽然很多人把注意力放在酒精如何 改变控制啮齿动物血压的神经、内分泌和内在心血管机制， 人们对慢性酒精如何改变人体阻力动脉的认识存在很大差距。 消耗，无论是在功能上还是在其基本的分子组成方面。有趣的是， 被称为sigma受体-1和-2的伴侣蛋白已被证明：1)是酒精的调节器 啮齿动物的饮酒行为，以及2)在血管组织中也有丰富的表达，具有改变的能力 平滑的肌肉收缩。因此，调节Sigma受体活性并降低 临床前模型中的酒精摄入还可能提供加速酒精逆转的额外好处-- 诱发性高血压。另一方面，由于目前对 Sigma受体在血管功能中的特定作用，也有可能使新的研究进展成为可能 旨在减少酒精摄入量的针对Sigma受体的治疗实际上可能会加剧 对酗酒者的高血压，并限制了这一有希望的方法的有效性。考虑到这一点，总体上 目前应用的目的是确定Sigma受体在酒精诱导中的可能作用 高血压。中心假设是长期饮酒促进Sigma受体介导的 阻力动脉中肾上腺素能受体信号的放大。建议进行这项研究的理由是 了解长期饮酒如何影响Sigma受体的表达、信号转导和功能 阻力动脉将允许对未来靶向治疗策略的安全性做出明智的决定 西格玛受体治疗酒精成瘾。在稳健的初步数据的指导下，核心假设将是 测试有两个特定的目标。目的1是确定血管平滑肌中不同的Sigma受体信号。 伴随着慢性酒精使用的人体阻力动脉反应性的肌肉潜在变化。目标2是 研究酒精对血管内皮细胞Sigma受体信号转导的影响。实验性的 如果没有，终点将是从器官捐赠者那里获得的人肠系膜动脉的功能反应性。 和Sigma受体调节剂的存在，将未确认的酒精使用和供体历史联系起来 其他因素包括性别和高血压，加上蛋白质组趋势和非编码RNA的变化 发生在与酒精使用水平有关的阻力动脉中。拟议研究的贡献将是 意义重大，因为它将第一次直接评估长期饮酒对 人类阻力动脉的内在活性和蛋白质组组成。建议的研究具有创新性。 因为这与用啮齿动物研究慢性酒精如何 使用影响血管功能，同时解决了Sigma受体在血管组织中的新作用。