Pathogenetic role of eNOS uncoupling in cardiopulmonary disorders

Abstract

The homodimeric flavohemeprotein endothelial nitric oxide synthase (eNOS) oxidizes l-arginine to l-citrulline and nitric oxide (NO), which acutely vasodilates blood vessels and inhibits platelet aggregation. Chronically, eNOS has a major role in the regulation of blood pressure and prevention of atherosclerosis by decreasing leukocyte adhesion and smooth muscle proliferation. However, a disturbed vascular redox balance results in eNOS damage and uncoupling of oxygen activation from l-arginine conversion. Uncoupled eNOS monomerizes and generates reactive oxygen species (ROS) rather than NO. Indeed, eNOS uncoupling has been suggested as one of the main pathomechanisms in a broad range of cardiovascular and pulmonary disorders such as atherosclerosis, ventricular remodeling, and pulmonary hypertension. Therefore, modulating uncoupled eNOS, in particular eNOS-dependent ROS generation, is an attractive therapeutic approach to preventing and/or treating cardiopulmonary disorders, including protective effects during cardiothoracic surgery. This review provides a comprehensive overview of the pathogenetic role of uncoupled eNOS in both cardiovascular and pulmonary disorders. In addition, the related therapeutic possibilities such as supplementation with the eNOS substrate l-arginine, volatile NO, and direct NO donors as well as eNOS modulators such as the eNOS cofactor tetrahydrobiopterin and folic acid are discussed in detail.

Retracted: ‘Fenofibrate improves the impaired endothelial progenitor cell function through inhibiting eNOS uncoupling in diabetic mice’ by Zhao et al.

“…Under the condition of eNOS uncoupling, eNOS itself can produce O 2 -instead of NO (Gielis et al, 2011). In the present study, we found that NO level was decreased and O 2 -production was increased in EPCs of diabetic mice.…”

Loss of Collectrin, an Angiotensin-Converting Enzyme 2 Homolog, Uncouples Endothelial Nitric Oxide Synthase and Causes Hypertension and Vascular Dysfunction

“…24,25 We next compared baseline levels of eNOS dimer and monomer in the aorta and kidney cortex and medulla. In these tissues, eNOS dimer and dimer/monomer ratios were significantly lower in collectrin KO mice compared with WT ( Figure 3B), suggesting that there is an altered balance of active and inactive eNOS in collectrin KO mice that favors a state of increased O 2…”

Concomitant Phosphodiesterase 5 Inhibition Enhances Myocardial Protection by Inhaled Nitric Oxide in Ischemia-Reperfusion Injury

“…Conversely, NO may interact with superoxide radicals to generate peroxynitrites and partially offset cardioprotection or may scavenge free radicals and transiently reduce nitrosative stress, as suggested by reduced cardiac 3-nitrotyrosine levels in the early post-reperfusion phase in mice treated with inhaled NO (Fig. 4D) (Ferdinandy et al, 2000;Szabó et al, 2007;Gielis et al, 2011).…”