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. 2022 Aug:152:113201.
doi: 10.1016/j.biopha.2022.113201. Epub 2022 May 27.

Plasmatic renin-angiotensin system in normotensive and hypertensive patients hospitalized with COVID-19

Mauro G Silva  1 , Gerardo R Corradi  1 , Juan I Pérez Duhalde  2 , Myriam Nuñez  3 , Eliana M Cela  4 , Daniel H Gonzales Maglio  4 , Ana Brizzio  2 , Martin R Salazar  2 , Walter G Espeche  2 , Mariela M Gironacci  5
Affiliations

Plasmatic renin-angiotensin system in normotensive and hypertensive patients hospitalized with COVID-19

Mauro G Silva et al. Biomed Pharmacother. 2022 Aug.

Abstract

Background: Besides its counterbalancing role of the renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE) 2 is the receptor for the type 2 coronavirus that causes severe acute respiratory syndrome, the etiological agent of COVID-19. COVID-19 is associated with increased plasmatic ACE2 levels, although conflicting results have been reported regarding angiotensin (Ang) II and Ang-(1-7) levels. We investigated plasmatic ACE2 protein levels and enzymatic activity and Ang II and Ang-(1-7) levels in normotensive and hypertensive patients hospitalized with COVID-19 compared to healthy subjects.

Methods: Ang II and Ang-(1-7), and ACE2 activity and protein levels were measured in 93 adults (58 % (n = 54) normotensive and 42 % (n = 39) hypertensive) hospitalized with COVID-19. Healthy, normotensive (n = 33) and hypertensive (n = 7) outpatient adults comprised the control group.

Results: COVID-19 patients displayed higher ACE2 enzymatic activity and protein levels than healthy subjects. Within the COVID-19 group, ACE2 activity and protein levels were not different between normotensive and hypertensive-treated patients, not even between COVID-19 hypertensive patients under RAS blockade treatment and those treated with other antihypertensive medications. Ang II and Ang-(1-7) levels significantly decreased in COVID-19 patients. When COVID-19 patients under RAS blockade treatment were excluded from the analysis, ACE2 activity and protein levels remained higher and Ang II and Ang-(1-7) levels lower in COVID-19 patients compared to healthy people.

Conclusions: Our results support the involvement of RAS in COVID-19, even when patients under RAS blockade treatment were excluded. The increased circulating ACE2 suggest higher ACE2 expression and shedding.

Keywords: Angiotensin; Angiotensin receptor blockers; Angiotensin-converting enzyme 2; Angiotensin-converting enzyme inhibitors; COVID-19; Hypertension.

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Conflict of interest statement

All authors have participated in the work and have reviewed and agree with the content of the article. None of the article contents are under consideration for publication in any other journal or have been published in any journal. The authors declare that there are no conflicts of interest.

Figures

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Graphical abstract
Fig. 1
Fig. 1
sACE2 activity and protein levels in healthy subjects and hospitalized COVID-19 patients: (A) sACE2 activity and (B) sACE2 protein levels in the plasma of healthy subjects (no COVID, n = 40) and hospitalized COVID-19 patients (COVID, n = 93); non-hypertensive (NT no COVID, n = 33) and hypertensive (HT no COVID) healthy subjects (n = 7); and non-hypertensive (NT COVID, n = 54) and hypertensive (HT) hospitalized COVID-19 patients (n = 39). The bottom and top of the box plots represent the 25th and 75th percentiles, respectively. The bands within the boxes show the median values and the whiskers extending from both ends of the boxes are minimum and maximum values. Wilcoxon Test (Mann-Whitney U) test was applied for statistical analysis.
Fig. 2
Fig. 2
sACE2 activity and protein levels in hospitalized COVID-19 patients excluding those under RAS blockade treatment: (A) sACE2 activity and (B) sACE2 protein levels in the plasma of healthy subjects (no COVID, n = 33) and hospitalized COVID-19 patients (COVID, n = 66), excluding those hypertensive hospitalized COVID-19 patients treated with RAS inhibitors. The bottom and top of the box plots represent the 25th and 75th percentiles, respectively. The bands within the boxes show the median values and the whiskers extending from both ends of the boxes are minimum and maximum values. Wilcoxon Test (Mann-Whitney U) test was applied for statistical analysis.
Fig. 3
Fig. 3
Ang II and Ang-(1−7) levels and Ang-(1−7)/Ang II ratio in hospitalized COVID-19 patients. (A) Ang II and (B) Ang-(1−7) levels and (E) Ang-(1−7)/Ang II ratio in the plasma of healthy subjects (no COVID, n = 33) and hospitalized COVID-19 patients (COVID, n = 66), excluding those hospitalized COVID-19 patients treated with RAS inhibitors. (C) Ang II and (D) Ang-(1−7) levels in the plasma of non-hypertensive healthy subjects (NT no COVID, n = 33) and non-hypertensive hospitalized COVID-19 patients (NT COVID, n = 54). The bottom and top of the box plots represent the 25th and 75th percentiles, respectively. The bands within the boxes show the median values and the whiskers extending from both ends of the boxes are minimum and maximum values. Wilcoxon test (Mann-Whitney U-test) was applied for statistical analysis.
Fig. 4
Fig. 4
Plasmatic ILs levels in hospitalized COVID-19 patients: (A) IL-6, (B) IL-8, (C) IL-1β, and (D) IL-10 levels in the plasma of healthy subjects (no COVID, n = 33) and hospitalized COVID-19 patients (COVID, n = 93), The bottom and top of the box plots represent the 25th and 75th percentiles, respectively. The bands within the boxes show the median values and the whiskers extending from both ends of the boxes are minimum and maximum values. Wilcoxon Test (Mann-Whitney U) test was applied for statistical analysis.
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