Soluble Angiotensin Converting Enzyme 2 (ACE2) Is Upregulated and Soluble Endothelial Nitric Oxide Synthase (eNOS) Is Downregulated in COVID-19-induced Acute Respiratory Distress Syndrome (ARDS).

Alice G Vassiliou,Alexandros Zacharis,Maria Pratikaki,Chrysi Keskinidou,Edison Jahaj,Parisis Gallos,Ioanna Dimopoulou,Anastasia Kotanidou,Stylianos E Orfanos

doi:10.3390/ph14070695

Abstract

A damaged endothelium is an underlying condition of the many complications of COVID-19 patients. The increased mortality risk associated with diseases that have underlying endothelial dysfunction, such as acute respiratory distress syndrome (ARDS), suggests that endothelial (e) nitric oxide synthase (NOS)-derived nitric oxide could be an important defense mechanism. Additionally, intravenous recombinant angiotensin converting enzyme 2 (ACE2) was recently reported as an effective therapy in severe COVID-19, by blocking viral entry, and thus reducing lung injury. Very few studies exist on the prognostic value of endothelium-related protective molecules in severe COVID-19 disease. To this end, serum levels of eNOS, inducible (i) NOS, adrenomedullin (ADM), soluble (s) ACE2 levels, and serum (s) ACE activity were measured on hospital admission in 89 COVID-19 patients, hospitalized either in a ward or ICU, of whom 68 had ARDS, while 21 did not. In our cohort, the COVID-19-ARDS patients had considerably lower eNOS levels compared to the COVID-19 non-ARDS patients. On the other hand, sACE2 was significantly higher in the ARDS patients. iNOS, ADM and sACE activity did not differ. Our results might support the notion of two distinct defense mechanisms in COVID-19-derived ARDS; eNOS-derived nitric oxide could be one of them, while the dramatic rise in sACE2 may also represent an endogenous mechanism involved in severe COVID-19 complications, such as ARDS. These results could provide insight to therapeutical applications in COVID-19.

Highlights

Several vasoconstrictors and vasodilators are produced by the vascular endothelium, such as endothelin-1, angiotensin-2, nitric oxide, and prostacyclin
The increased mortality risk associated with diseases that have underlying endothelial dysfunction, such as acute respiratory distress syndrome (ARDS), suggests that Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) could be an important defense mechanism
It is worth mentioning that from the linear regression model applied, soluble eNOS and sACE2 levels were not dependent on age, sex, or comorbidities, and seemed to be statistically significantly dependent only on the presence of ARDS (p < 0.05). None of these circulating biomarkers correlated with a prolonged stay

Summary

Introduction

Several vasoconstrictors and vasodilators are produced by the vascular endothelium, such as endothelin-1, angiotensin-2, nitric oxide, and prostacyclin. These vasoactive substances play a role in the regulation of the vasomotor tone, the recruitment and function of inflammatory cells, and the regulation of thrombosis [1]. In acute respiratory distress syndrome (ARDS), the balance is shifted from pulmonary vasodilators towards vasoconstrictors, resulting in increased pulmonary vascular resistance and pulmonary hypertension [2,3]. A damaged endothelial system is an underlying condition of the many complications experienced by COVID-19 patients. Endothelial cells act as a barrier that must be breached before progression to severe disease. Endothelial nitric oxide synthase (eNOS) is an Pharmaceuticals 2021, 14, 695.

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