Recoupling the cardiac nitric oxide synthases: tetrahydrobiopterin synthesis and recycling.
Nitric oxide (NO), a key regulator of cardiovascular function, is synthesized from L-arginine and oxygen by the enzyme nitric oxide synthase (NOS). This reaction requires tetrahydrobiopterin (BH4) as a cofactor. BH4 is synthesized from guanosine triphosphate (GTP) by GTP cyclohydrolase I (GTPCH) and recycled from 7,8-dihydrobiopterin (BH2) by dihydrofolate reductase. Under conditions of low BH4 bioavailability relative to NOS or BH2, oxygen activation is "uncoupled" from L-arginine oxidation, and NOS produces superoxide (O                            (2)                                      (-)                         ) instead of NO. NOS-derived superoxide reacts with NO to produce peroxynitrite (ONOO(-)), a highly reactive anion that rapidly oxidizes BH4 and propagates NOS uncoupling. BH4 depletion and NOS uncoupling contribute to overload-induced heart failure, hypertension, ischemia/reperfusion injury, and atrial fibrillation. L-arginine depletion, methylarginine accumulation, and S-glutathionylation of NOS also promote uncoupling. Recoupling NOS is a promising approach to treating myocardial and vascular dysfunction associated with heart failure.
Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Matthew S
MS
Alkaitis
Mark J
MJ
Crabtree
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism / Q000627:therapeutic use; D003067:Coenzymes / Q000378:metabolism; D003326:Coronary Circulation / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
D003067:Coenzymes; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; C017226:7,8-dihydrobiopterin; D019001:Nitric Oxide Synthase; C003402:sapropterin