Amelioration and Reversal of Hypertension by Thioredoxin

硫氧还蛋白改善和逆转高血压

• 批准号: 9156261
• 负责人: KUMUDA C DAS
• 金额: $ 58.04万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2016-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9156261
• 关键词: 2 year old; Age-Years; Aging; Aneurysm; Antihypertensive Agents; Antioxidants; Arteries; Attenuated; Biological Preservation; Blood Pressure; Blood Vessels; Cardiac; Cardiovascular Diseases; Cells; Chronic; Clinical; Data; Development; Disease; Elderly; Endothelium; Figs - dietary; Foundations; Functional disorder; Genotype; Goals; Health; Heart Hypertrophy; Heart failure; Human; Hypertension; Hypotension; Impairment; Individual; Injection of therapeutic agent; Knockout Mice; Left Ventricular Hypertrophy; Life; Mediating; Mesenteric Arteries; Modeling; Mus; NOS3 gene; Nitric Oxide; Oxidation-Reduction; Papio; Pathogenesis; Phenotype; Phosphorylation; Population; Prevention; Property; Proteins; Recombinants; Relaxation; Research; Risk; Risk Factors; Role; Stroke; Sudden Death; Superoxides; System; TXN gene; Testing; Time; Transgenic Mice; Validation; Wild Type Mouse; abstracting; age related; aged; base; bench to bedside; blood pressure reduction; blood pressure regulation; endothelial dysfunction; genetic regulatory protein; high risk; hypertension control; hypertension treatment; improved; in utero; in vivo; insight; lifetime risk; mouse model; nonhuman primate; normotensive; novel; novel strategies; novel therapeutics; overexpression; oxidation; preclinical study; prevent; receptor; response; restoration; tetrahydrobiopterin; therapeutic development; vascular endothelial dysfunction

Abstract Hypertension is a major risk factor for cardiovascular diseases, and especially poses health problems for people with advancing age. However, the pathogenesis of hypertension and the basic mechanism of blood pressure responses are incompletely understood. Thioredoxin is a multifunctional redox regulatory protein with powerful antioxidant properties that is essential for life as thioredoxin knockout mice die in utero. We recently developed a transgenic mouse line that is deficient in functional thioredoxin (dnTrx-Tg), and a complementary line that overexpresses the human protein (Trx-Tg). Unexpectedly, we observed that older (>2 years) dnTrx-Tg and wild-type mice showed markedly decreased arterial relaxation and high blood pressure, while aged-Trx-Tg mice continued to function normally with normal blood pressure. This hypertensive phenotype of dnTrx-Tg mice and anti-hypertensive phenotype of Trx-Tg mice prompted us to further evaluate these genotypes. Based on our preliminary data we hypothesize that Trx prevents age-dependent high blood pressure by maintaining arterial relaxation via increased eNOS expression and activation, and by upregulating the AT2R receptor. In Aim 1 we will evaluate the role of vascular redox state of in control of hypertension in the three genotypes, in Aim 2 we will determine the effect of Trx on eNOS expression and function, and in Aim 3 we will evaluate the mechanism of AT2R-dependent endothelium cell dysfunction in aged mice and how the receptor is regulated by Trx. We will also use an aged baboon model for validation our mice data. These studies will provide insight into blood pressure control in the elderly population, and will lay the groundwork for therapeutic development of thioredoxin.

摘要 高血压是心血管疾病的主要危险因素， 老年人的健康问题。然而， 高血压和血压反应的基本机制是不完全的 明白硫氧还蛋白是一种多功能氧化还原调节蛋白，具有强大的功能 抗氧化特性是生命所必需的，因为硫氧还蛋白敲除小鼠在子宫内死亡。 我们最近开发了一种功能性硫氧还蛋白缺乏的转基因小鼠品系 （dnTrx-Tg）和过表达人蛋白质的互补系（Trx-Tg）。 出乎意料的是，我们观察到年龄较大（>2岁）的dnTrx-Tg和野生型小鼠显示出 显着降低动脉舒张和高血压，而老龄-Trx-Tg小鼠 血压正常，功能正常。这种高血压表型 的dnTrx-Tg小鼠和抗高血压表型的Trx-Tg小鼠促使我们进一步 评估这些基因型。根据我们的初步数据，我们假设Trx 通过维持动脉舒张来预防年龄依赖性高血压， 增加eNOS表达和激活，并通过上调AT 2 R受体。在 目的：1、探讨血管氧化还原状态在高血压控制中的作用。 三种基因型，在目标2中，我们将确定Trx对eNOS表达的影响， 在目的3中，我们将评估AT 2 R依赖性内皮细胞的机制， 老年小鼠的细胞功能障碍以及Trx如何调节受体。我们还将使用 一个老年狒狒模型来验证我们的小鼠数据。这些研究将提供洞察力 老年人的血压控制，并将为 硫氧还蛋白的治疗进展。