With prevalence higher than 33% in United States, hypertension is a major risk factor contributing to cardiovascular diseases (CVD) and global mortality, hence remaining an increasingly important medical and public health issue. According to the Veterans? Affairs (VA) Office of Research & Development, CVD, including hypertension, are the number-one killer in the USA, the leading cause of hospitalization in the VA health care system and a major cause of disability. Recent studies have documented that hypertension occurs at a younger age than it used to, now affecting individuals of deployment age and future veterans. Hypertension is also important to Veterans because it affects 60 percent of people over age 65 and it is associated with a number of diseases, like diabetes, and lifestyle habits, like smoking, that contribute to its development. The role of the brain renin-angiotensin system (RAS) in the maintenance of normal blood pressure (BP) and in the neuro-cardiovascular dysregulation leading to hypertension has been firmly established. Angiotensin (Ang)-II, by means of its type 1 receptor (AT1R), promotes increased sympathetic activity, salt and water reabsorption, vasoconstriction, aldosterone and vasopressin release and inflammation, all contributing to hypertension. Angiotensin Converting Enzyme type 2 (ACE2), one of the latest identified members of this system plays a compensatory role to the activation of the RAS. Numerous studies have shown that ACE2 overexpression prevents experimental hypertension. However, our laboratory reported that Ang-II mediates ACE2 internalization and degradation via AT1R activation, effects that were prevented by pretreatment with leupeptin, a lysosomal inhibitor. The detailed mechanism leading to the loss of ACE2 compensatory activity has not been investigated. This proposal aims at targeting this new mechanism responsible for ACE2 down-regulation, originally described by our group, to design innovative strategies for the treatment of hypertension. The efficacy of these strategies will be evaluated by their ability to prevent ACE2 internalization and preserve ACE2 compensatory in the context of neurogenic hypertension. Our preliminary data, show that ubiquitination of the C-terminus of ACE2 is a major mechanism leading to ACE2 degradation. In addition, stimulation of the ?-arrestin pathway with an AT1R-biased agonist increased ACE2 activity in neurons. Finally, ACE2 internalization may involve other members of the G-protein coupled receptor family (GPCR), like bradykinin B1 receptors (B1R) interacting with the RAS. Thus, the hypothesis of this work is that AT1R and B1R blunts ACE2 compensatory activity through multiple binding partners affecting its expression levels, subcellular localization and enzymatic activity. Pharmacological and genetic targeting of these binding partners may constitute a novel approach to maintain ACE2 compensatory activity and reduce hypertension. To test this hypothesis, we will use state-of-the-art in vitro and in vivo, molecular, cellular and pharmacological tools combined with unique transgenic and knockout models of hypertension. The results of the present investigation will provide new therapeutic approaches for the treatment of hypertension and a new set of tools for the VA health care system.

Public Health Relevance

The brain renin-angiotensin system (RAS) has major deleterious effects in the development and maintenance of cardiovascular diseases (CVD), notably in hypertension, the leading cause of hospitalization in the VA health care system and a major cause of disability. Based on our preliminary results, we propose new strategies to target hypertension that will be evaluated on their ability to preserve angiotensin converting enzyme 2 (ACE2) activity, an enzyme that attenuates the negative effects of RAS activation in hypertension and CVD. These strategies will be investigated both in vitro and in vivo in order to determine their overall impact on the treatment of hypertension.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX004294-01
Application #
9563789
Study Section
Cardiovascular Studies B (CARB)
Project Start
2018-07-01
Project End
2022-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Southeast Louisiana Veterans Health Care
Department
Type
DUNS #
828108790
City
New Orleans
State
LA
Country
United States
Zip Code
70161