Dr. Eric Lazartigues Presents “ACE2 Internalization: From Hypertension to COVID-19” for Dean's Seminar
>Dr. Eric Lazartigues recently presented “ACE2 Internalization: From Hypertension to COVID-19” for the School of Medicine Dean's Seminar.
The presentation started off with evidence for the beneficial effects of ACE2 expression in hypertensive conditions, namely the counter regulatory effect of Angiotensin-II degradation by ACE2. In hypertensive conditions, however, ACE2 expression is reduced in various tissues, thus limiting ACE2 compensatory activity.
Two mechanisms of ACE2 downregulation were then introduced: ACE2 shedding by ADAM17 from the cell surface, that Dr. Lazartigues' group highlighted a decade ago, and ACE2 internalization discovered in collaboration with Dr. Catalin Filipeanu at Howard University. Details were presented showing how ACE2 internalization is dependent on the Angiotensin-II type-1 receptor and appeared to involve ubiquitination, a mechanism first reported by this group.
In the absence of related data in the literature, an effort was initiated to identify ACE2 ubiquitination partners in hypertension by taking advantage of the LSU Proteomics Core. Combined proteomics and bioinformatics data pointed to UBR1 as a potential E3 ligase responsible for the addition of ubiquitin moieties to ACE2 and BRCC36 as a likely deubiquitinase working to restore the protein's native structure and limit its degradation. Various models of experimental hypertension were then used to validate these targets. Sex differences were unexpectedly identified and confirmed in cardiac samples from organ donations, in partnership with Dr. Andreas Beyer at the Medical College of Wisconsin.
Notably, UBR1 was shown to be dramatically upregulated in hypertensive conditions, in a testosterone-dependent manner. On the other hand, BRCC36 was shown to be highly expressed in females and to be downregulated by hypertension and the reduction of estrogen levels. Additionally, high levels of ACE2 were identified in males, as well as a strong reduction in hypertension. Dr. Lazartigues pointed out that these data, although promising, were only associative and that causality had to be further investigated. Using cell culture models, he showed that either silencing UBR1 or overexpressing BRCC36 resulted in increased ACE2 expression and that in these conditions, Ang-II was no longer able to promote ACE2 internalization, thus confirming the ability of these targets to modulate ACE2 ubiquitination.
These findings were then brought into the context of SARS-CoV-2 infection. The group formed the hypothesis that pre-existing conditions such as hypertension, type-2 diabetes and obesity are associated with an upregulation of the renin-angiotensin system and that the coronavirus could possibly take advantage of the ACE2 internalization pathway to further infect cells. Recently published cell culture data were then presented showing that the SARS-CoV-2 spike 1 protein could indeed promote ACE2 internalization, a mechanism dependent on the expression of Ang-II type-1 receptor, as it could be blocked by FDA-approved Ang-II receptor blockers.
The presentation concluded by emphasizing the potential role of ACE2 ubiquitination partners as potential targets for the treatment of resistant hypertension and how preventing ACE2 internalization could be beneficial in reducing SARS-CoV-2 infection and preventing COVID-19.
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