Intraplatelet L-Arginine-Nitric Oxide Metabolic Pathway: From Discovery to Clinical Implications in Prevention and Treatment of Cardiovascular Disorders.

Jakub Gawrys,Ewa Szahidewicz-Krupska,Adrian Doroszko,Damian Gajecki

doi:10.1155/2020/1015908

Abstract

Despite the development of new drugs and other therapeutic strategies, cardiovascular disease (CVD) remains still the major cause of morbidity and mortality in the world population. A lot of research, performed mostly in the last three decades, revealed an important correlation between “classical” demographic and biochemical risk factors for CVD, (i.e., hypercholesterolemia, hyperhomocysteinemia, smoking, renal failure, aging, diabetes, and hypertension) with endothelial dysfunction associated directly with the nitric oxide deficiency. The discovery of nitric oxide and its recognition as an endothelial-derived relaxing factor was a breakthrough in understanding the pathophysiology and development of cardiovascular system disorders. The nitric oxide synthesis pathway and its regulation and association with cardiovascular risk factors were a common subject for research during the last decades. As nitric oxide synthase, especially its endothelial isoform, which plays a crucial role in the regulation of NO bioavailability, inhibiting its function results in the increase in the cardiovascular risk pattern. Among agents altering the production of nitric oxide, asymmetric dimethylarginine—the competitive inhibitor of NOS—appears to be the most important. In this review paper, we summarize the role of L-arginine-nitric oxide pathway in cardiovascular disorders with the focus on intraplatelet metabolism.

Highlights

After establishing the real nature of EDRF by Furchgott et al [1, 2], which appeared to be nitric oxide (NO), numerous other groups were working on the nitric oxide synthesis pathway and its potential role in humanphysiology
This led to the discovery of the nitric oxide synthase [3] which produces nitric oxide from L-arginine with flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), tetrahydrobiopterin (BH4), and heme with a zinc atom as cofactors
Numerous functions of NO were established which can generally be divided into three groups: (1) Group associated with neuronal transmission, where the NO plays an inhibitory role as a mediator in peripheral nonadrenergic noncholinergic (NANC)

Summary

Introduction

After establishing the real nature of EDRF by Furchgott et al [1, 2], which appeared to be nitric oxide (NO), numerous other groups were working on the nitric oxide synthesis pathway and its potential role in human (patho)physiology. This led to the discovery of the nitric oxide synthase [3] which produces nitric oxide from L-arginine with flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), tetrahydrobiopterin (BH4), and heme with a zinc atom as cofactors. (2) Group playing an inflammatory role, where NO is produced by the inducible isoform of nitric oxide synthase (iNOS)

Nitric Oxide in Cardiovascular Disorders

ADMA as the Most Potent Inhibitor of the L-Arginine-Nitric Oxide Pathway

The Role of ADMA in Cardiovascular

Findings

Conclusions