Pathogenetic role of eNOS uncoupling in cardiopulmonary disorders

Free Radic Biol Med. 2011 Apr 1;50(7):765-76. doi: 10.1016/j.freeradbiomed.2010.12.018. Epub 2010 Dec 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Arginine / metabolism*
  • Arginine / pharmacology
  • Arginine / therapeutic use
  • Atherosclerosis / drug therapy
  • Atherosclerosis / metabolism
  • Atherosclerosis / physiopathology
  • Biopterin / analogs & derivatives
  • Biopterin / pharmacology
  • Biopterin / therapeutic use
  • Blood Pressure / drug effects
  • Cardiac Surgical Procedures / adverse effects
  • Cell Adhesion / drug effects
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiopathology
  • Folic Acid / pharmacology
  • Folic Acid / therapeutic use
  • Humans
  • Hypertension, Pulmonary / drug therapy
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / physiopathology
  • 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 / metabolism
  • Reactive Oxygen Species / adverse effects
  • Reactive Oxygen Species / metabolism
  • Vasodilation / drug effects
  • Ventricular Remodeling / drug effects


  • Nitric Oxide Donors
  • Reactive Oxygen Species
  • Biopterin
  • Nitric Oxide
  • Folic Acid
  • Arginine
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • sapropterin
  • Oxygen