Amelioration and Reversal of Hypertension by Thioredoxin

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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.