title: Targeting endothelial and myocardial dysfunction with tetrahydrobiopterin.
abstract: Tetrahydrobiopterin (BH(4)) is an essential cofactor for aromatic amino acid hydroxylases and for all three nitric oxide synthase (NOS) isoforms. It also has a protective role in the cell as an antioxidant and scavenger of reactive nitrogen and oxygen species. Experimental studies in humans and animals demonstrate that decreased BH(4)-bioavailability, with subsequent uncoupling of endothelial NOS (eNOS) plays an important role in the pathogenesis of endothelial dysfunction, hypertension, ischemia-reperfusion injury, and pathologic cardiac remodeling. Synthetic BH(4) is clinically approved for the treatment of phenylketonuria, and experimental studies support its capacity for ameliorating cardiovascular pathophysiologies. To date, however, the translation of these studies to human patients remains limited, and early results have been mixed. In this review, we discuss the pathophysiologic role of decreased BH(4) bioavailability, molecular mechanisms regulating its metabolism, and its potential therapeutic use as well as pitfalls as an NOS-modulating drug. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''
authors: Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Dept. of Cardiology, Maastricht, The Netherlands. an.moens@mumc.nl
authors: An L
authors: AL
authors: Moens
authors: Rinrada
authors: R
authors: Kietadisorn
authors: Judy Y
authors: JY
authors: Lin
authors: David
authors: D
authors: Kass
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000188:drug therapy; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009206:Myocardium / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D007527:Isoenzymes; D001708:Biopterins; D019001:Nitric Oxide Synthase; C003402:sapropterin