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Principal Investigator: Eric D Lazartigues
Organization: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
Fiscal Year: 2022
Funding agency: Veterans Affairs
The current COVID-19 pandemic is one of the most disruptive events in human history, caused by the SARS-
CoV-2 virus, member of the coronavirus family that uses angiotensin converting enzyme 2 (ACE2), a
transmembrane carboxypeptidase identified as a member of the renin-angiotensin system (RAS) as an entry
point to the cells. Clinical reports suggest that pre-existing conditions such as hypertension, diabetes and obesity
predispose to COVID-19 mortality. Considering that these co-morbidities are highly prevalent in Veterans and
active duty personnel, these populations are at high risk of infection by SARS-CoV-2. The role of the brain RAS
in the maintenance of normal blood pressure (BP) and in the neuro-cardiovascular dysregulation leading to
hypertension has been firmly established. In addition, anosmia (loss of smell) is an early symptom of COVID-19
suggesting the brain is a primary target for SARS-CoV-2 infection. For the treatment of hypertension, two of the
most popular drug choices are ACE inhibitors (ACEI) and angiotensin-II (Ang-II) type 1 receptor (AT1R) blockers
(ARB). None of these classes of drugs have a direct effect on ACE2 activity, but there is evidence indicating that
they may alter long-term ACE2 expression levels and subcellular localization, suggesting that patients taking
these medications may be subject to more severe infections with SARS-CoV-2. Thus, clear data on the
relationship between ACE2 plasma membrane levels, SARS-CoV-2 and co-expression of other RAS members
are required to promptly adapt the therapy in this subset of patients. Beyond establishing ACE2 as a critical
player in the prevention of neurogenic hypertension, our group was the first to report that Ang-II mediates ACE2
internalization and degradation via AT1R activation. Thus, the hypothesis of this proposal is that ACE2-AT1R
complexes enhance SARS-CoV-2 infection in hypertensive Veterans while RAS blockers prevent ACE2
internalization and coronavirus infection. Taking advantage of unique resources, including a humanized
transgenic mouse expressing human ACE2 constitutively, we will determine whether AT1R contribute to SARS-
CoV-2 infection and whether ACEI and ARB reduce the incidence of COVID-19.
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