Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension.
Endothelial dysfunction in the setting of cardiovascular risk factors such as hypercholesterolemia, diabetes mellitus, chronic smoking, as well hypertension, is, at least in part, dependent of the production of reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of nitric oxide (NO). ROS-producing enzymes involved in increased oxidative stress within vascular tissue include NADPH oxidase, xanthine oxidase, and mitochondrial superoxide producing enzymes. Superoxide produced by the NADPH oxidase may react with NO, thereby stimulating the production of the NO/superoxide reaction product peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, therefore switching an antiatherosclerotic NO producing enzyme to an enzyme that may accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and also occurs within the smooth muscle cell layer. Increased superoxide production has important consequences with respect to signaling by the soluble guanylate cyclase and the cGMP-dependent kinase I, which activity and expression is regulated in a redox-sensitive fashion. The present review will summarize current concepts concerning eNOS uncoupling, with special focus on the role of tetrahydrobiopterin in mediating eNOS uncoupling.
Schulz
Eberhard
E
II Medizinische Klinik, Mainz, Kardiologie, Angiologie und Internistische Intensivmedizin, Mainz, Germany.
Jansen
Thomas
T
Wenzel
Philip
P
Daiber
Andreas
A
Münzel
Thomas
T
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase
D018160:Receptors, Cytoplasmic and Nuclear; D030421:Peroxynitrous Acid; D001708:Biopterins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C003402:sapropterin