Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers

Abstract

Rationale: Angiotensin-converting enzyme 2 (ACE2) is the main entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but how SARS-CoV-2 interactions with ACE2 influences the renin-angiotensin system (RAS) in Coronavirus disease 2019 (COVID-19) is unknown. Objective: To measure circulating ACE2 and ACE levels in COVID-19 patients and investigate associations with risk factors, outcome and inflammatory markers. Methods and results: Soluble ACE2 (sACE2) and sACE concentrations were measured by ELISA in plasma samples from 114 hospital-treated COVID-19 patients and 10 healthy controls. Follow-up samples after four months were available for 58/114 patients. Von Willebrand factor (VWF), factor VIII (fVIII), D-dimer, interleukin 6 (IL-6), tumor necrosis factor α and plasminogen activator inhibitor 1 (PAI-1) had previously been determined. Levels of sACE2 were higher in COVID-19 patients than in healthy controls, median 5.0 (interquartile range 2.8-11.8) ng/ml versus 1.4 (1.1-1.6) ng/ml, p < 0.0001. sACE2 was higher in men than women, but were not affected by other risk factors for severe COVID-19. sACE2 decreased to 2.3 (1.6-3.9) ng/ml at follow-up, p < 0.0001, but remained higher than in healthy controls, p=0.012. Follow-up sACE2 levels were higher with increasing age, BMI, total number of comorbidities, for patients with diabetes and patients on RAS-inhibition. sACE was marginally lower during COVID-19 compared with at follow-up, 57 (45-70) ng/ml versus 72 (52-87) ng/ml, p=0.008. Levels of sACE2 and sACE did not differ depending on survival or disease severity (care level, respiratory support). sACE2 during COVID-19 correlated with VWF, fVIII and D-dimer, while sACE correlated with IL-6, TNFα and PAI-1. Conclusions: sACE2 was transiently elevated in COVID-19, likely due to increased shedding from infected cells. sACE2 and sACE during COVID-19 differed distinctly in their correlations with markers of inflammation and endothelial dysfunction, suggesting release from different cell types and/or vascular beds.

Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients

“…SARS-CoV-2 uses ACE2 as a functional receptor for entry into cells [ 32 ]. Circulating ACE2 is increased in patients with active COVID-19 infection compared with healthy controls [ 21 – 23 ]. Our analysis is the first description of circulating ACE2 in association with clinical outcomes in patients with COVID-19 disease.…”

Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?

“…However, chronic upregulation of IL-10 has also been shown to contribute to inflammatory diseases ( Lauw et al, 2000 ; Lu et al, 2021 ; Yaseen et al, 2020 ), thus suggesting that an initial and persistent secretion of immunosuppressive IL-10 could trigger a subsequent compensatory inflammatory response, as it may occur in the late phase of severe COVID-19. In line with this hypothesis, in COVID-19 patients, sACE (but not sACE2), which is initially lower than healthy individuals, has been shown to significantly increase with time and to display positive correlations with IL-6 and TNF-α inflammatory cytokines ( Lundström et al, 2021 ). In this regard, the so called cytokine storm is mediated by increased levels of several proinflammatory cytokines, among which TNF-α and IL-1β have been shown to induce ACE2 synthesis and/or shedding ( Clarke et al, 2014 ; Hong et al, 2009 ) that further increase sACE2 systemic release and activity, which, in this case, are independent of SARS-CoV-2 binding.…”

“…A confirmation that SARS-CoVs can induced an ACE2 hyperactivity comes from recent reports showing an increase of systemic ACE2 activity in COVID-19 patients and in accordance to disease severity ( Nagy et al, 2021 ; Patel et al, 2021 ; Reindl-Schwaighofer et al, 2021 ). Similarly, high circulating levels of sACE2 were significantly associated with worse or longer COVID-19 outcome in hospitalized patients ( Kragstrup et al, 2021 ; Lundström et al, 2021 ; Reindl-Schwaighofer et al, 2021 ). Notably, in healthy individuals circulating ACE2 activity is usually undetectable ( Lew et al, 2008 ), instead pre-existing high levels of circulating ACE2 protein/activity are typical of patients with comorbidities (e.g.…”

“…Differently, in severe COVID-19, plasma concentrations of Ang II have been shown to be significantly higher than healthy controls (see ( Liu et al, 2020b )), and they were particularly higher during the initial days of hospitalisation as compared with those observed during late days [median 165.7 pmol/L, IQR, 61.2–680.6 vs median 95.7, IQR, 37.5–250.0 ( Reindl-Schwaighofer et al, 2021 ),], suggesting that during the early days of hospitalisation, severe COVID-19 patients had a disease progression characterised by upregulation of both renin and ACE (a feature of the second dangerous phase of COVID-19). Indeed, COVID-19 patients (compared with healthy individuals) initially had lower levels of the soluble form of ACE, which significantly increase at follow-up (four months after the first test) ( Lundström et al, 2021 ). Therefore, the reduction of Ang II levels observed during the late days of hospitalisation may be consistent with a further increase of ACE2 activity (a feature of the final phase of COVID-19).…”

An Overview of Adipose Tissue ACE2 Modulation by Diet and Obesity. Potential Implications in COVID-19 Infection and Severity

“…In addition, it has also been observed that soluble ACE2 may contribute to COVID-19 susceptibility, although its significance remains uncertain. In this sense, subjects with obesity and patients with COVID-19 have higher serum ACE2 levels [ 56 , 57 , 58 , 59 ]. The increased soluble ACE2 levels in COVID-19 patients may result from the cellular lysis that occurs when a severe infection takes place.…”