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.

高血压是造成全球疾病负担的最重要的危险因素，而且比例很大