Recoupling the cardiac nitric oxide synthases: Tetrahydrobiopterin synthesis and recycling

Journal article

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 (O2 -) 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. © Springer Science+Business Media, LLC 2012.

Authors: Alkaitis, MS; Alkaitis, MS; Crabtree, M

• Journal: Current Heart Failure Reports
• Volume: 9
• Issue: 3
• Pages: 200-210
• Publication date: 2012-09-01
• DOI: 10.1007/s11897-012-0097-5
• EISSN: 1546-9549
• ISSN: 1546-9530