Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities.
The endothelium is essential for the maintenance of vascular homeostasis. Central to this role is the production of endothelium-derived nitric oxide (EDNO), synthesized by the endothelial isoform of nitric oxide synthase (eNOS). Endothelial dysfunction, manifested as impaired EDNO bioactivity, is an important early event in the development of various vascular diseases, including hypertension, diabetes, and atherosclerosis. The degree of impairment of EDNO bioactivity is a determinant of future vascular complications. Accordingly, growing interest exists in defining the pathologic mechanisms involved. Considerable evidence supports a causal role for the enhanced production of reactive oxygen species (ROS) by vascular cells. ROS directly inactivate EDNO, act as cell-signaling molecules, and promote protein dysfunction, events that contribute to the initiation and progression of endothelial dysfunction. Increasing data indicate that strategies designed to limit vascular ROS production can restore endothelial function in humans with vascular complications. The purpose of this review is to outline the various ways in which ROS can influence endothelial function and dysfunction, describe the redox mechanisms involved, and discuss approaches for preventing endothelial dysfunction that may highlight future therapeutic opportunities in the treatment of cardiovascular disease.
Thomas
Shane R
SR
Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia. shane.thomas@unsw.edu.au
Witting
Paul K
PK
Drummond
Grant R
GR
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014652:Vascular Diseases / Q000378:metabolism / Q000628:therapy*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014157:Transcription Factors; D013481:Superoxides; D009569:Nitric Oxide; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D052250:Nitric Oxide Synthase Type III; D011494:Protein Kinases; D010744:Phosphoric Monoester Hydrolases