Angiotensin-(1-7) and Cardiovascular Derangements in Obesity Hypertension

PROJECT SUMMARY Obesity is a global epidemic that is associated with sympathetic overactivation, endothelial dysfunction, and insulin resistance; all of which can contribute to hypertension development. Despite well-established clinical associations, the mechanisms connecting obesity with hypertension remain poorly understood, with several antihypertensive therapies eliciting detrimental metabolic effects. This illustrates the need to identify new targets with a positive metabolic profile for treatment of obesity hypertension. We propose that angiotensin-(1- 7), a protective hormone of the renin-angiotensin system, provides this ideal target. In support of this concept, we have shown that acute and chronic angiotensin-(1-7) treatment reduces cardiovascular sympathetic tone and blood pressure and improves endothelial function and insulin sensitivity in obese mouse models. There is limited clinical data, however, with no information on systemic effects of angiotensin-(1-7) on cardiovascular or metabolic outcomes in any patient population including obesity hypertension. To address this critical gap, we obtained preliminary data in obese hypertensive subjects suggesting that: circulating angiotensin-(1-7) levels are reduced and negatively correlate with blood pressure; acute intravenous angiotensin-(1-7) infusion reduces blood pressure and may increase endothelial-dependent vasodilation and decrease sympathetic tone; and angiotensin-(1-7) may improve insulin sensitivity, findings consistent with the positive metabolic effects seen in animal models. Based on these data, this proposal will test the central hypothesis that angiotensin-(1-7) improves cardiovascular and metabolic-related derangements in obesity hypertension. We propose proof-of- concept mechanistic studies to examine the cardiovascular and metabolic effects of acute intravenous angiotensin-(1-7) infusion in obese hypertensive subjects. We will test hypotheses that angiotensin-(1-7) can: reduce sympathetic activity and blood pressure; improve endothelial function; and increase whole-body insulin sensitivity and insulin-mediated microvascular recruitment. A sub-study will also be performed in pure autonomic failure patients lacking autonomic modulation of blood pressure to determine if angiotensin-(1-7) blood pressure and vasodilatory effects are via direct actions on the vasculature versus indirect engagement of autonomic mechanisms. Any results obtained from these studies will be novel and will increase mechanistic understanding of the role of angiotensin-(1-7) in the etiology of obesity hypertension.