Vascular Redox Signaling, Endothelial Nitric Oxide Synthase Uncoupling, and Endothelial Dysfunction in the Setting of Transportation Noise Exposure or Chronic Treatment with Organic Nitrates

Abstract

Significance: Cardiovascular disease and drug-induced health side effects are frequently associated with—or even caused by—an imbalance between the concentrations of reactive oxygen and nitrogen species (RONS) and antioxidants, respectively, determining the metabolism of these harmful oxidants. Recent Advances: According to the “kindling radical” hypothesis, the initial formation of RONS may further trigger the additional activation of RONS formation under certain pathological conditions. The present review specifically focuses on a dysfunctional, uncoupled endothelial nitric oxide synthase (eNOS) caused by RONS in the setting of transportation noise exposure or chronic treatment with organic nitrates, especially nitroglycerin (GTN). We further describe the various “redox switches” that are proposed to be involved in the uncoupling process of eNOS. Critical Issues: In particular, the oxidative depletion of tetrahydrobiopterin and S-glutathionylation of the eNOS reductase domain are highlighted as major pathways for eNOS uncoupling upon noise exposure or GTN treatment. In addition, oxidative disruption of the eNOS dimer, inhibitory phosphorylation of eNOS at the threonine or tyrosine residues, redox-triggered accumulation of asymmetric dimethylarginine, and l -arginine deficiency are discussed as alternative mechanisms of eNOS uncoupling. Future Directions: The clinical consequences of eNOS dysfunction due to uncoupling on cardiovascular disease are summarized also, providing a template for future clinical studies on endothelial dysfunction caused by pharmacological or environmental risk factors.

Metabolic reprogramming, oxidative stress, and pulmonary hypertension

“…Uncoupling of eNOS can occur through various mechanisms, including suboptimal levels of the substrate l -arginine or the cofactor tetrahydrobiopterin (BH 4 ), decreased dimerization, or increased levels of the endogenous NOS inhibitor asymmetric dimethylarginine [ 191 ]. Phosphorylation at Threonine 495 increases eNOS uncoupling [ 191 , 192 ] and has been linked to metabolic reprogramming in the lung endothelium [ 192 , 193 ], suggesting that eNOS uncoupling is associated with altered mitochondrial metabolism. The mechanism of eNOS uncoupling is still being explored.…”

Health position paper and redox perspectives - Disease burden by transportation noise

“…Due to the excessive superoxide formation in noise-exposed animals, endothelial NOS (eNOS) in the aorta (and nNOS in the brain) uncouples, which means that it transforms into a source of O 2 •− and H 2 O 2 rather than, or in addition to • NO source ( Fig. 14 ) [ 45 , 405 ]. NOS uncoupling was previously demonstrated in tissues of noise-exposed mice by dihydroethidium staining in the presence of the eNOS inhibitor N G -nitro- l -arginine methyl ester ( l -NAME) [ 16 , 247 , 281 ].…”

Dietary Nitrate from Plant Foods: A Conditionally Essential Nutrient for Cardiovascular Health

“…Different physiological conditions, especially those associated with pathophysiological processes such as inflammation present in certain disease states, as well as the complex biochemistry of distinct biological compartments, dictate the metabolic disposition of these pathways. As such, the NO axis responds to endogenous (NOS-dependent NO production) and exogenous (dietary nitrate and nitrite; organic nitrates such as nitroglycerin) inputs, local redox conditions, and local oxygen tension [ 20 ].…”