Human Resistance Artery Functional Changes with Alcohol Use

高血压是全球疾病负担的单一最重要的风险因素， 高血压的发病原因是饮酒。虽然人们一直在关注酒精是如何 改变啮齿类动物控制血压的神经、内分泌和内在心血管机制， 关于慢性酒精如何改变人体阻力动脉的知识存在很大的空白， 消费，无论是功能上和在其潜在的分子组成方面。有趣的是 已知为σ受体-1和σ受体-2的伴侣蛋白已经显示：1）是酒精的调节剂 啮齿类动物的饮水行为，以及2）在血管组织中也大量表达，具有改变 平滑肌收缩因此，有可能调节σ受体活性并降低σ受体活性的药物是有效的。 临床前模型中的酒精摄入也可能提供加速酒精逆转的额外益处， 诱发性高血压另一方面，由于目前在知识方面存在重大差距， σ受体在血管功能中的特定作用，也可能是新的 以σ受体为靶点的旨在减少酒精摄入的治疗剂实际上可能加剧 酗酒者的高血压，并限制了这种有前途的方法的实用性。考虑到这一点， 本申请的目的是确定σ受体在酒精诱导的神经细胞凋亡中的假定作用。 高血压核心假设是长期饮酒促进了σ受体介导的 阻力动脉中肾上腺素能受体信号的放大。拟议研究的基本原理是 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， 阻力动脉将允许对未来治疗策略的安全性做出明智的决定， sigma受体来治疗酒精成瘾在可靠的初步数据的指导下，中心假设将是 测试有两个具体目标。目的1是确定血管平滑肌细胞中的差异σ受体信号转导， 慢性饮酒导致的人体阻力动脉反应性的肌肉潜在变化。目标二是 研究酒精诱导的血管内皮σ受体信号传导的变化。实验 终点将是从器官供体获得的人肠系膜动脉的功能反应性， 和σ受体调节剂的存在，与酒精使用的去识别供体历史相关， 其他因素包括性别和高血压，加上蛋白质组学趋势和非编码RNA的变化， 发生在阻力动脉与酒精使用水平有关。拟议研究的贡献将 这是重要的，因为它将提供第一个直接评估慢性酒精使用对健康的影响。 人阻力动脉内在活性和蛋白质组组成。该研究具有创新性 因为它与使用啮齿动物研究慢性酒精如何影响的现状有很大不同 使用影响血管功能，同时解决了σ受体在血管组织中的新作用。

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.