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

Abstract

The main entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is angiotensin‐converting enzyme 2 (ACE2). SARS‐CoV‐2 interactions with ACE2 may increase ectodomain shedding but consequences for the renin‐angiotensin system and pathology in Coronavirus disease 2019 (COVID‐19) remain unclear. We measured soluble ACE2 (sACE2) and sACE levels by enzyme‐linked immunosorbent assay in 114 hospital‐treated COVID‐19 patients compared with 10 healthy controls; follow‐up samples after four months were analyzed for 58 patients. Associations between sACE2 respectively sACE and risk factors for severe COVID‐19, outcome, and inflammatory markers were investigated. 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 < .0001. sACE2 was higher in men than women but was 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 < .0001, but remained higher than in healthy controls, p = .012. sACE was marginally lower during COVID‐19 compared with at follow‐up, 57 (45–70) ng/ml versus 72 (52–87) ng/ml, p = .008. Levels of sACE2 and sACE did not differ depending on survival or disease severity. sACE2 during COVID‐19 correlated with von Willebrand factor, factor VIII and D‐dimer, while sACE correlated with interleukin 6, tumor necrosis factor α, and plasminogen activator inhibitor 1. Conclusions: sACE2 was transiently elevated in COVID‐19, likely due to increased shedding from infected cells. sACE2 and sACE during COVID‐19 differed in correlations with markers of inflammation and endothelial dysfunction, suggesting release from different cell types and/or vascular beds.

Quantifying Renin-Angiotensin-System Alterations in COVID-19

“…The meta-analysis that we carried out in the previous section has shed some light on these questions to a certain extent, but many points remain obscure. Indeed, the experimental and clinical data that we collected from the literature about e.g., the levels of proteins and peptides involved in RAS and the activity of the enzymes, partially disagree [79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94].…”

“…We review here recent data about measurements of RAS components in COVID-19. For that purpose, we manually collected and screened a series of clinical and experimental results from [79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94], listed in Supplementary Table S1. The individuals enrolled in these studies were classified into two or three classes: COVID-19 patients or severe and moderate COVID-19 patients, and controls or asymptomatic patients.…”

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.…”

Defective efferocytosis as a predictor of COVID-19 mortality

“…Recent studies demonstrated that ADAM-17-driven soluble ACE2 (sACE2) levels are elevated in COVID-19 patients. The binding of SARS-CoV-2 by sACE2 may enable cell entry of tissues where membrane-bound ACE2 (mACE2) is poorly expressed [65,66]. Low expression levels of mACE2 and associated higher ADAM-17 activity have been related with cardiovascular diseases.…”

“…According to this perspective, while mACE2 may mediate cell entry of SARS-CoV-2, a genetically modified soluble form of ACE2, called human recombinant soluble angiotensin-converting enzyme-2 (hrsACE2), may decrease cell entry of SARS-CoV-2 competing for mACE2 [95]. However, the plasma RAS balance in COVID-19 patients was already characterized by a strong transient increase in circulating plasma sACE2 [66]. Therefore, in COVID-19 patients with comorbid diseases, both Angiotensin II and virus adversely affect the prognosis by affecting the RAS balance in a way that down-regulates ACE2 [96].…”