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.
Highlights
The coronavirus enters host cells via its surface spike protein that binds to angiotensin-converting enzyme 2 (ACE2) through its receptor binding domain where it is proteolytically activated by human proteases allowing for cell entry
Both ARG isozymes are expressed in human endothelial cell (EC), and they effectively compete with eNOS for substrate arginine, leading to reductions in nitric oxide (NO) synthesis and elevations in superoxide formation secondary to the uncoupling of eNOS [12–18,70]
There is an increase in ARG1 expression with COVID-19 that shifts the metabolism of arginine away from the synthesis of NO towards the formation of ornithine, polyamines, and proline
Summary
Semi-essential amino acid that plays an important role in regulating immune and vascular cell function [12,13]. ARG1 is a cytosolic enzyme that is highly expressed in the liver where catalyzes the final step of the urea cycle. Arginine depletion by ARG limits the translation of iNOS by activating the general control nonderepressible 2 (GCN2) kinase, while ARG-derived spermine inhibits the expression of iNOS, leading to further reductions of NO production [28,29]. The NOS-derived intermediate product N-ω-hydroxy-L-arginine directly inhibits ARG activity, whereas iNOS-formed NO selectively stimulates ARG1 activity by nitrosylating cysteine residues of the protein [30,31]. These two arginine-metabolizing enzymes show reciprocal and regulatory interactions that impact their activity
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