key: cord-0702239-wkn1b5mc authors: Green, Shawn J. title: Covid-19 accelerates endothelial dysfunction and nitric oxide deficiency date: 2020-05-16 journal: Microbes Infect DOI: 10.1016/j.micinf.2020.05.006 sha: 09cb8b62abf384889fdcc93d8cbf0ad5f2737738 doc_id: 702239 cord_uid: wkn1b5mc nan Martel and colleagues provide a thoughtful review on strategies to increase airway nitric oxide to treat and possibly prevent Covid-19 [1] . However, it is becoming apparent that the clinical presentation of Covid-19 begins with acute respiratory distress in the lungs that moves quickly to vascular networks throughout the gut, kidney, heart, and brain with associated platelet-endothelial dysfunction and abnormally rapid life-threatening blood clotting [2] . SARS-CoV-2 is emerging as a thrombotic and vascular disease targeting endothelial cells throughout the body and is particularly evident in patients with cardiometabolic comorbidities, in particular hypertension, with associated endothelial dysfunction [3] . A hallmark of endothelial dysfunction and thrombotic events is suppressed endothelial nitric oxide synthase (eNOS) with concomitant nitric oxide deficiency. In healthy vessels, the endothelium releases the vasodilator and antithrombotic factor, nitric oxide. Whereas in injured vessels, nitric oxide is impaired contributing hypertension and thrombus formation [4] . Restoring nitric oxide, independent of eNOS, may counter endotheliitis and contribute to pulmonary vasodilatation, antithrombotic, and direct antiviral activity [5] . As to the later, nitric oxide reportedly interferes with the interaction between coronavirus viral S-protein and its cognate host receptor, ACE-2. Nitric oxide-mediated S-nitrosylation of viral cysteine proteases and serine protease, TMPRSS2, which are critical in viral cellular entry and also appear to be nitric oxide sensitive [6, 7, 8, 9, 10] . Based on a report of improved lung function during the 2003 SARS outbreak, FDA's emergency expanded use of nitric oxide gas is now underway for treating Covid-19 [1] . Alternatively, dietary inorganic nitrate has been shown in multiple studies to be effective at restoring endothelial function, reducing pulmonary and arterial hypertension, and promoting antimicrobial activity [5] . It is well understood that dietary inorganic nitrates is bio-converted to nitric oxide through a series of well-defined steps beginning with the friendly microflora on the tongue reducing nitrate to nitrite, which is subsequently reduced to nitric oxide in the gut, blood stream, and various organs, including the lung. The formation of inorganic nitrite and S-nitrosothiols is absorbed into the circulation where it acts as a transitory storage pool for subsequent nitric oxide production [11] . The conversion of inorganic nitrite to nitric oxide is expedited in conditions of acidosis or hypoxemia which occurs in regions of the pulmonary vasculature in lungs of COPD patients and those that exhibit acute respiratory distress syndrome as observed in coronavirus infected lungs. Reportedly, consumption of inorganic nitrate for 8 days in COPD population increased lung nitric oxide by 200% and reduced respiratory symptoms [12] . Restoring nitric oxide through dietary inorganic nitrate may be a consideration for prevention and early treatment which would operate at two-levels: reverse plateletendothelial dysfunction and associated thrombosis as well as lower viral burden [1, 5, 11, 14] . Could nitric oxide help to prevent or treat COVID-19? Microbes Infect How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes Endothelial cell infection and endotheliitis in Covid-19 The role of nitric oxide on endothelial function Nitric oxide in mucosal immunity Dual effect of nitric oxide on SARS-CoV replication: viral RNA production and palmitoylation of the S protein are affected An antiviral mechanism of nitric oxide: inhibition of a viral protease SARS-CoV-2 Cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Alterations of tumor microenvironment by nitric oxide impedes castration-resistant prostate cancer growth A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry Strategies to increase nitric oxide signaling in cardiovascular disease Influence of dietary nitrate supplementation on lung function and exercise gas exchange in COPD patients Acute ingestion of beetroot juice increases exhaled nitric oxide in healthy individuals Antimicrobial and immunopathologic effects of cytokineinduced nitric oxide synthesis