Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

Abstract

Coronavirus disease 2019 (COVID-19) represents a major public health crisis that has caused the death of nearly six million people worldwide. Emerging data have identified a deficiency of circulating arginine in patients with COVID-19. Arginine is a semi-essential amino acid that serves as key regulator of immune and vascular cell function. Arginine is metabolized by nitric oxide (NO) synthase to NO which plays a pivotal role in host defense and vascular health, whereas the catabolism of arginine by arginase to ornithine contributes to immune suppression and vascular disease. Notably, arginase activity is upregulated in COVID-19 patients in a disease-dependent fashion, favoring the production of ornithine and its metabolites from arginine over the synthesis of NO. This rewiring of arginine metabolism in COVID-19 promotes immune and endothelial cell dysfunction, vascular smooth muscle cell proliferation and migration, inflammation, vasoconstriction, thrombosis, and arterial thickening, fibrosis, and stiffening, which can lead to vascular occlusion, muti-organ failure, and death. Strategies that restore the plasma concentration of arginine, inhibit arginase activity, and/or enhance the bioavailability and potency of NO represent promising therapeutic approaches that may preserve immune function and prevent the development of severe vascular disease in patients with COVID-19.

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial

“…Several nutritional supplements and bioactive foods are being investigated to counteract long COVID [ 9 ]. l -arginine is a key regulator of immune, respiratory, and endothelial function [ 10 , 11 ]. Its pleiotropic properties are regulated by two main metabolizing enzymes, nitric oxide (NO) synthase and arginase [ 12 ].…”

“…The flux of l -arginine towards NO synthesis is associated with beneficial effects on immune and vascular health, while its catabolism to ornithine by arginase has been associated with an abnormal immune response and endothelial dysfunction [ 13 , 14 ]. Accumulating evidence indicates that l -arginine metabolism is altered in patients with COVID-19 [ 10 , 11 ]. During acute COVID-19, the upregulation of arginase activity reduces the circulating levels of l -arginine and shifts its metabolism away from NO production to induce immune and endothelial dysfunction, inflammation, and thrombosis, which ultimately lead to vascular occlusion and multiorgan failure [ 11 ].…”

“…Accumulating evidence indicates that l -arginine metabolism is altered in patients with COVID-19 [ 10 , 11 ]. During acute COVID-19, the upregulation of arginase activity reduces the circulating levels of l -arginine and shifts its metabolism away from NO production to induce immune and endothelial dysfunction, inflammation, and thrombosis, which ultimately lead to vascular occlusion and multiorgan failure [ 11 ]. Indeed, lower plasma levels of l -arginine and higher arginase activity have been found both in patients with COVID-19 and in children with the multisystem inflammatory syndrome (MIS-C) compared with healthy controls [ 15 ].…”

“…Based on these observations, strategies to restore circulating levels of l -arginine and increase NO bioavailability have been proposed to counteract immune, respiratory, and vascular complications of COVID-19 [ 11 , 18 ]. Vitamin C may support the beneficial effects of l -arginine on endothelial function by increasing intracellular tetrahydrobiopterin, a co-factor needed for the oxidation of l -arginine to NO, in endothelial cells [ 12 , 19 ].…”

Arginase: shedding light on the mechanisms and opportunities in cardiovascular diseases

“…Furthermore, large amount of ARG1 + G-MDSC cells was found in the lungs of patients who died from COVID-19 complications, which might deplete L-arginine, leading to impaired T cell receptor and endothelial function [ 135 ]. Additionally, numerous investigations based on metabolomics analysis identified lower L-arginine levels in plasma of patients with COVID-19, indicating an increase in arginase activity in these patients [ 136 ]. Another clinical study also discovered that circulating level of ADMA in COVID-19 patients is significantly higher, impairing the bioavailability of L-arginine [ 137 ].…”