Pathogenetic role of eNOS uncoupling in cardiopulmonary disorders

• Published in: Free radical biology & medicine Vol. 50; no. 7; pp. 765 - 776
• Main Authors: Gielis, Jan F., Lin, Judy Y., Wingler, Kirstin, Van Schil, Paul E.Y., Schmidt, Harald H., Moens, An L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2011
• Subjects: adhesion; Arginine - metabolism; Arginine - pharmacology; Arginine - therapeutic use; atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Atherosclerosis - physiopathology; Biopterins - analogs & derivatives; Biopterins - pharmacology; Biopterins - therapeutic use; blood pressure; Blood Pressure - drug effects; blood vessels; Cardiac Surgical Procedures - adverse effects; Cardioprotection; Cell Adhesion - drug effects; citrulline; endothelial nitric oxide synthase; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; eNOS modulators; eNOS uncoupling; folic acid; Folic Acid - pharmacology; Folic Acid - therapeutic use; Free radicals; Humans; hypertension; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - physiopathology; leukocytes; nitric oxide; Nitric Oxide - metabolism; Nitric Oxide - pharmacology; Nitric Oxide - therapeutic use; Nitric Oxide Donors - pharmacology; Nitric Oxide Donors - therapeutic use; Nitric Oxide Synthase Type III - metabolism; Oxidation-Reduction; oxygen; Oxygen - metabolism; platelet aggregation; protective effect; reactive oxygen species; Reactive Oxygen Species - adverse effects; Reactive Oxygen Species - metabolism; respiratory tract diseases; smooth muscle; Superoxide; surgery; Tetrahydrobiopterin; Vasodilation - drug effects; Ventricular Remodeling - drug effects; Superoxide; Cardioprotection; Free radicals; Tetrahydrobiopterin; eNOS modulators; eNOS uncoupling
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2010.12.018

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.