Cardiovascular Effects of Angiotensin-(1-7) in Obesity Hypertension
Description: Obesity is a major public health concern that greatly increases risk for developing cardiovascular disease. Importantly, obesity is associated with endothelial dysfunction and elevated sympathetic tone, vascular and autonomic derangements known to elevate blood pressure (BP) and increase cardiovascular risk. The renin-angiotensin system may explain cardiovascular complications in obesity. Circulating angiotensin (Ang) II levels are increased in obesity and known to promote endothelial dysfunction and sympathetic activation to elevate BP. Blocking Ang II activity with ACE inhibitors and Ang receptor blockers are often used in obese clinical populations to reduce these deleterious cardiovascular effects. It is less well appreciated that these treatments also increase levels of Ang-(1-7), a vasodilatory hormone that opposes Ang II actions. Ang-(1-7) is reduced in obese and hypertensive animal models and restoration of this hormone improves endothelial function and reduces sympathetic activity, which may contribute to its BP-lowering effects. Our preliminary data show that chronic Ang-(1-7) treatment attenuates hypertension in obese mice, perhaps in part by reducing sympathetic tone. Furthermore, our data show that circulating Ang-(1-7) is reduced in obese hypertensive humans and that acute infusion of this hormone decreases systolic BP by ~9 mmHg and plasma norepinephrine levels by ~20% in this population. There is limited clinical data for Ang-(1-7), however, with no published studies in obesity. In this proposal, we will test the overall hypothesis that Ang-(1-7) improves cardiovascular function in humans with obesity hypertension. We will test this hypothesis in a randomized, double blind, placebo-controlled crossover study utilizing an integrative cardiovascular physiological approach. We will investigate the effects of acute intravenous Ang-(1-7) infusion on endothelial-mediated vasodilation in the brachial and coronary arteries (Aim 1) and on BP and muscle sympathetic nerve activity with direct microneurography recordings (Aim 2) in obese hypertensive humans. The findings from these studies will enhance our understanding of the role of renin-angiotensin mechanisms in the etiology of obesity hypertension, to hopefully lead to new treatments to target beneficial cardiovascular outcomes.
Funder: American Heart Association
Amount: $103,300
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2018-07-01
End date: 2020-06-30
Investigators: Amanda Miller, Amanda Miller
Institution: The Pennsylvania State University College of Medicine
Funded outputs count: 4
Funder award ID: 18POST33960087
OpenAlex ID: G7875017600