title: 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.
authors.affiliation: Department of Vascular and Thoracic Surgery, University of Antwerp, Antwerp, Belgium.
authors.forename: Jan F
authors.initials: JF
authors.lastname: Gielis
authors.forename: Judy Y
authors.initials: JY
authors.lastname: Lin
authors.forename: Kirstin
authors.initials: K
authors.lastname: Wingler
authors.forename: Paul E Y
authors.initials: PE
authors.lastname: Van Schil
authors.forename: Harald H
authors.initials: HH
authors.lastname: Schmidt
authors.forename: An L
authors.initials: AL
authors.lastname: Moens
mesh_terms: D001120:Arginine / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D006348:Cardiac Surgical Procedures / Q000009:adverse effects; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005492:Folic Acid / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000009:adverse effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D001708:Biopterins; D009569:Nitric Oxide; D005492:Folic Acid; D001120:Arginine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin; D010100:Oxygen