title: Regulation of endothelial cell tetrahydrobiopterin pathophysiological and therapeutic implications.
abstract: Tetrahydrobiopterin (BH(4)) is a critical cofactor for the nitric oxide synthases. In the absence of BH(4), these enzymes become uncoupled, fail to produce nitric oxide, and begin to produce superoxide and other reactive oxygen species (ROS). BH(4) levels are modulated by a complex biosynthetic pathway, salvage enzymes, and by oxidative degradation. The enzyme GTP cyclohydrolase-1 catalyzes the first step in the de novo synthesis of BH(4) and new evidence shows that this enzyme is regulated by phosphorylation, which reduces its interaction with its feedback regulatory protein (GFRP). In the setting of a variety of common diseases, such as atherosclerosis, hypertension, and diabetes, reactive oxygen species promote oxidation of BH(4) and inhibit expression of the salvage enzyme dihydrofolate reductase (DHFR), promoting accumulation of BH(2) and NOS uncoupling. There is substantial interest in therapeutic approaches to increasing tissue levels of BH(4), largely by oral administration of this agent. BH(4) treatment has proved effective in decreasing atherosclerosis, reducing blood pressure, and preventing complications of diabetes in experimental animals. While these basic studies have been very promising, there are only a few studies showing any effect of BH(4) therapy in humans in treatment of these common problems. Whether BH(4) or related agents will be useful in treatment of human diseases needs additional study.
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Decatur, Georgia, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Sergey
authors.initials: S
authors.lastname: Dikalov
authors.forename: Li
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans
chemical_list: D001708:Biopterins; C003402:sapropterin