Amelioration and Reversal of Hypertension by Thioredoxin

摘要 高血压是心血管疾病的主要危险因素，尤其是体位 高龄人群的健康问题。然而，该病的发病机制 高血压和血压反应的基本机制是不完整的 明白了。硫氧还蛋白是一种多功能氧化还原调节蛋白，具有强大的 当硫氧还蛋白基因敲除小鼠在子宫中死亡时，对生命至关重要的抗氧化特性。 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系 (dnTrx-Tg)和一个过度表达人类蛋白的补充系(Trx-Tg)。 出乎意料的是，我们观察到年龄较大(&gt；2岁)的dnTrx-TG和野生型小鼠显示 显著降低动脉松弛和高血压，而老龄TRX-TG小鼠 继续功能正常，血压正常。这种高血压表型 DnTrx-Tg小鼠的降压表型和Trx-Tg小鼠的降压表型促使我们进一步 评估这些基因类型。根据我们的初步数据，我们假设Trx 通过维持动脉松弛来预防年龄依赖性高血压 增加eNOS的表达和激活，并上调AT2R受体。在……里面 目的1我们将评估血管氧化还原状态在高血压控制中的作用。 在目标2中，我们将确定Trx对eNOS和eNOS表达的影响 功能，在目标3中，我们将评估AT2R依赖的内皮细胞的机制 衰老小鼠的细胞功能障碍以及Trx如何调节该受体。我们还将使用 一种用于验证我们的老鼠数据的老年狒狒模型。这些研究将提供洞察力 进入老年人群的血压控制，并将为 硫氧还蛋白的治疗进展。

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.