Implications of SARS-Cov-2 infection on eNOS and iNOS activity: Consequences for the respiratory and vascular systems

Abstract

Symptoms of COVID-19 range from asymptomatic/mild symptoms to severe illness and death, consequence of an excessive inflammatory process triggered by SARS-CoV-2 infection. The diffuse inflammation leads to endothelium dysfunction in pulmonary blood vessels, uncoupling eNOS activity, lowering NO production, causing pulmonary physiological alterations and coagulopathy. On the other hand, iNOS activity is increased, which may be advantageous for host defense, once NO plays antiviral effects. However, overproduction of NO may be deleterious, generating a pro-inflammatory effect. In this review, we discussed the role of endogenous NO as a protective or deleterious agent of the respiratory and vascular systems, the most affected in COVID-19 patients, focusing on eNOS and iNOS roles. We also reviewed the currently available NO therapies and pointed out possible alternative treatments targeting NO metabolism, which could help mitigate health crises in the present and future CoV's spillovers.

Keywords: Acute respiratory distress syndrome; Antiviral effect; Coagulopathy; Coronavirus disease-19; Nitric oxide metabolism.

Graphical abstract

Fig. 1

Implications of ARDS in hypoxic pulmonary vasoconstriction (HPV). (A) In individuals with intact endothelium, alveolar hypoxia induces vasoconstriction in intrapulmonary arteries, redirecting blood flow to well ventilated areas. The blood pressure in arteries near ventilated alveoli rises, which in turn promotes shear stress, induces eNOS activity and increases the concentration of endothelium-derived vasodilators, like NO, inhibiting HPV and promoting widening of vessel diameter. This regulation causes the blood to flow in direction of well-ventilated areas, improving V/Q [[35], [36], [37]]. (B) In ARDS patients, the diffuse inflammation causes endothelial dysfunction in intrapulmonary arteries, causing reduction of HPV. In this situation, the production of endothelium-derived vasoconstrictors (endothelin and thromboxane) is disrupted, causing relaxation of vessel walls in underventilated areas. Once the blood flow is not redirected to well ventilated areas and the activation of eNOS by shear does not occur, inhibiting the production of endothelium-derived vasodilators. These events may cause redirection of blood flow to areas were gas exchange is compromised, worsening V/Q [34,38]. Created with BioRender.com.

Fig. 2

NO antiviral mechanisms, hypothesis of action on SARS-CoV-2 replication. (A) Acting on viral proteases. The processing of the polyprotein region is a point of posttranslational control that is essential for virus replication. SARS-CoV-2 processes the polyproteins using two cysteine proteases, the papain-like protease (PL^pro) or the chymotrypsin-like protease (M^pro). S-nitrosylation of specific Cys residue reduces the activity of these proteases inhibiting SARS-CoV-2 replication [106,107]. (B) Acting on host cell proteins. The complete intracellular life cycle of SARS-CoV-2 relies on interactions with host molecules. The proteolytic cleavage of S proteins by serine protease TMPRSS2 and cysteine proteases cathepsin B (CatB) and CatL is essential for the virus fusion. Thus, the inhibition CatB and CatL by S-nitrosylation could prevent SARS-CoV-2 entry into cell. (C) Furthermore, NO-mediated S-nitrosylation of cysteine-containing proteins may prevent virus molecular interactions critical for RNA replication, virus assembly and translation of viral mRNAs, abrogating SARS-CoV-2 cell cycle [108,109].