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.
Hypertension is a high risk factor for the onset of many cardiovascular diseases including heart failure, cardiac hypertrophy, stroke and sudden death, and this risk further increases with advancing age. We have found that high levels of thioredoxin, one of our own proteins can decrease hypertension in the elderly and this age-related hypertension could be reversed by treatment with thioredoxin. Our project seeks to understand the mechanisms associated with protection and reversal of age-related hypertension by thioredoxin that will help in the development new therapeutics for treatment of hypertension in the elderly.
|Hilgers, Rob H P; Kundumani-Sridharan, Venkatesh; Subramani, Jaganathan et al. (2017) Thioredoxin reverses age-related hypertension by chronically improving vascular redox and restoring eNOS function. Sci Transl Med 9:|