# New strategies to restore ACE2 compensatory activity in neurogenic hypertension

> **NIH VA I01** · SOUTHEAST LOUISIANA VETERANS HEALTH CARE · 2020 · —

## Abstract

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 β-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...

## Key facts

- **NIH application ID:** 9932897
- **Project number:** 5I01BX004294-03
- **Recipient organization:** SOUTHEAST LOUISIANA VETERANS HEALTH CARE
- **Principal Investigator:** Eric D Lazartigues
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932897

## Citation

> US National Institutes of Health, RePORTER application 9932897, New strategies to restore ACE2 compensatory activity in neurogenic hypertension (5I01BX004294-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932897. Licensed CC0.

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