The angiotensin II type 1 receptor blocker valsartan in the battle against COVID-19

INTRODUCTION

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) uses the host’s angiotensin-converting enzyme 2 (ACE2) as a cellular entry point. Therefore, ACE2 is pivotal in SARS-CoV-2 replication and viral shedding. ACE2 is part of the renin-angiotensin system (RAS), which appears to be a central player in the clinical outcomes of patients with coronavirus disease 2019 (COVID-19) ((1, 2)). Angiotensin (Ang)II is the main effector peptide of the RAS, which is converted by cleavage of AngI into AngII by the angiotensin-converting enzyme (ACE) ((3)). AngII has a high binding affinity for the AngII type 1 receptor (AT1R), thus increasing blood pressure, inflammation, fibrosis, and oxidative stress. ACE2 is the rate-limiting enzyme in the degradation of AngII, counteracting deleterious effects of AngII by converting AngII into Ang(1-7). SARS-CoV-2 reduces ACE2 activity, resulting in elevated (tissue) AngII concentrations, which appear to be associated with poor clinical outcomes. Therefore, modulating ACE2 expression/activity might impact SARS-CoV-2 viral replication, shedding, and the severity of complications in COVID-19 patients ((2)).

At the beginning of the SARS-CoV-2 pandemic, it was suggested that pharmacological blockade of the RAS by commonly used ACE inhibitors or AT1R blockers (ARBs) might increase the risk of SARS-CoV-2 infection because ACE inhibition and AT1R blockade might increase ACE2 expression/activity ((1, 2)). However, results from large observational and experimental studies have suggested that ACE inhibitors or ARBs are not associated with the risk of SARS-CoV-2 infection ((2)). Rather, RAS blockade might prove advantageous in COVID-19 because RAS blockade decreases detrimental effects of the ACE-AngII-AT1R axis and it may be beneficial through the ACE2-Ang(1-7)-mitochondrial assembly receptor axis. ARB treatment might be a promising strategy to also prevent SARS-CoV-2 infection, since ACE2 can enter cells only by AT1R-mediated endocytosis ((2, 4)). Currently, RAS-modulating drugs are being investigated as a therapeutic strategy in several clinical trials to prevent SARS-CoV-2 infection and to alleviate disease severity ((5)). Notably, excess adipose tissue (AT) in people with obesity might serve as a reservoir for SARS-CoV-2 spread, thus providing a link between obesity and the susceptibility to and severity of COVID-19 ((2, 6)). Therefore, the effects of RAS modulators on AT are worth exploring since RAS components are highly expressed in human AT.

Since it is unknown whether RAS blockade alters tissue-specific expression of RAS components in humans, here we investigated whether treatment with the ARB valsartan for 26 weeks alters the expression of RAS components, including ACE2, in human AT and skeletal muscle.

METHODS

We previously performed a randomized, double-blind, placebo-controlled clinical trial in which participants with impaired glucose metabolism received either the ARB valsartan (160 mg for first 2 weeks and 320 mg for subsequent 24 weeks) or placebo for 26 weeks (ISRCTN Registry: ISRCTN42786336) ((7)). The study was approved by the Medical-Ethical Committee of Maastricht University Medical Centre+ and performed according to the Declaration of Helsinki. Before and after the 26-week treatment, abdominal subcutaneous AT and skeletal muscle (m. vastus lateralis) biopsies were collected after an overnight fast (n = 36; BMI: 31.0 ± 0.8 kg/m²; systolic blood pressure: 128 ± 2 mmHg; and diastolic blood pressure: 80 ± 1 mmHg). Total RNA was extracted and stored at −80°C.

RESULTS AND DISCUSSION

We found no significant differences in the expression of AGT, ACE, ACE2, and AT1R in AT after 26 weeks of valsartan treatment compared with placebo (Figure 1A). In skeletal muscle also, no differences were found in AGT and ACE expression (Figure 1B). Unfortunately, expression of ACE2 and AT1R could not be reliably quantified in muscle. So far, data on plasma ACE2 activity and Ang(1-7) levels in patients without COVID-19 who have been treated with ACE inhibitors or ARBs are inconsistent; some studies have shown increased circulating ACE2 activity, whereas others have not ((1)). Our finding that ARB treatment did not alter AT ACE2 expression is in agreement with a recent report showing that ARB treatment has no significant effect on systemic ACE2 levels, either in COVID-19 patients or in controls ((8)). A limitation of the present study is the lack of data on systemic RAS components owing to unavailability of plasma samples. Notably, we cannot exclude that valsartan treatment alters RAS components, including ACE2, in people with (morbid) obesity, who usually present with higher RAS activity in AT ((2)). Likewise, it would be interesting to assess the effects of RAS blockade on AT expression of RAS components in patients with COVID-19.

In conclusion, we provide the first evidence that the ARB valsartan does not affect the expression of RAS genes in AT and skeletal muscle in humans with overweight. Our findings may help us to better understand the results of ongoing clinical trials investigating the effects of RAS blockade on clinical outcomes in patients with confirmed COVID-19. Given the increased risk of worse clinical outcomes after SARS-CoV-2 infection in people with obesity, further studies are warranted to investigate the effects of RAS blockade on ACE2 in AT in people with obesity and COVID-19.

CONFLICT OF INTEREST

The authors declared no conflict of interest.

CLINICAL TRIAL REGISTRATION

ISRCTN Registry, ISRCTN42786336.