Decreased availability of nitric oxide and hydrogen sulfide is a hallmark of COVID-19

Abstract

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is involved in a global outbreak affecting millions of people who manifest a variety of symptoms. Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is increasingly associated with cardiovascular complications requiring hospitalizations; however, the mechanisms underlying these complications remain unknown. Nitric oxide (NO) and hydrogen sulfide (H 2 S) are gasotransmitters that regulate key cardiovascular functions. Methods Blood samples were obtained from 68 COVID-19 patients and 33 controls and NO and H 2 S metabolites were assessed. H 2 S and NO levels were compared between cases and controls in the entire study population and subgroups based on race. The availability of gasotransmitters was examined based on severity and outcome of COVID-19 infection. The performance of H 2 S and NO levels in predicting COVID-19 infection was also analyzed. Multivariable regression analysis was performed to identify the effects of traditional determinants of gasotransmitters on NO and H 2 S levels in the patients with COVID-19 infection. Results Significantly reduced NO and H 2 S levels were observed in both Caucasian and African American COVID-19 patients compared to healthy controls. COVID-19 patients who died had significantly higher NO and H 2 S levels compared to COVID-19 patients who survived. Receiver-operating characteristic analysis of NO and H 2 S metabolites in the study population showed free sulfide levels to be highly predictive of COVID-19 infection based on reduced availability. Traditional determinants of gasotransmitters, namely age, race, sex, diabetes, and hypertension had no effect on NO and H 2 S levels in COVID-19 patients. Conclusion These observations provide the first insight into the role of NO and H 2 S in COVID-19 infection, where their low availability may be a result of reduced synthesis secondary to endotheliitis, or increased consumption from scavenging of reactive oxygen species.

Serum nitrite and nitrate: A potential biomarker for post-covid-19 complications?

“…Quite a few literatures have suggested that NO exerts its pathophysiological function mainly via S-nitrosylation, instead of via other pathways as shown in Scheme 2 . In one recent study by Dominic et al, S-nitrosothiol was significantly lower in the COVID-19 patients than in the control group [ 36 ]. It indicated that blood SNO levels changed during SARS-CoV-2 infection with uncovered mechanism yet.…”

“…However, conversely, in several reports, decreased basal NO production or bioavailability (normally in the 100–400 nM range) has been suggested to underlie elevated apoptosis of endothelial cells induced by SARS-CoV-2 infection, increased inflammation, or excessive reactive oxygen species (ROS) [ 23 , 24 , 35 ]. One recent study reported decreased total NO, nitrite and SNO in COVID-19 patients in hospital [ 36 ]. Another study in Spain showed that nitric oxide diffusion was reduced in around 40% patients discharged from hospital, via respiratory function tests with a MasterScreen PFT equipment [ 37 ].…”

Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome

“…Survivors reportedly exhibit higher serum levels of H 2 S and higher numbers of circulating lymphocytes ( 70 ); H 2 S stimulates T cell proliferation ( 71 ). Indeed, exogenous H 2 S therapy may be beneficial in mild to moderate COVID-19 disease ( 72 ).…”

COVID-19 generates hyaluronan fragments that directly induce endothelial barrier dysfunction

“…However, in aged individuals and those with cardiovascular disease such as diabetes and hypertension, the 2 most prevalent comorbidities in COVID-19, homeostatic endothelial functions become impaired ( 22 ). Clinical studies provide evidence that endothelial dysfunction is a major determinant of severe COVID-19, and patients have markers of endothelial injury, including increased levels of fibrinogen, fibrin degradation products, D-dimer, von Willebrand factor ( 23 , 24 ), and soluble thrombomodulin ( 15 ), as well as signatures of impaired endothelial function such as apoptotic ECs ( 17 ), decreased nitric oxide availability ( 25 ), and vascular leakage ( 26 ).…”