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Current Heart Failure Reports
Published in: Current Heart Failure Reports 3/2012

Open Access 01-09-2012 | Investigative Therapies (J.-L. Balligand, Section editor)

Recoupling the Cardiac Nitric Oxide Synthases: Tetrahydrobiopterin Synthesis and Recycling

Authors: Matthew S. Alkaitis, Mark J. Crabtree

Published in: Current Heart Failure Reports | Issue 3/2012

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Abstract

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.
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Metadata
Title
Recoupling the Cardiac Nitric Oxide Synthases: Tetrahydrobiopterin Synthesis and Recycling
Authors
Matthew S. Alkaitis
Mark J. Crabtree
Publication date
01-09-2012
Publisher
Current Science Inc.
Published in
Current Heart Failure Reports / Issue 3/2012
Print ISSN: 1546-9530
Electronic ISSN: 1546-9549
DOI
https://doi.org/10.1007/s11897-012-0097-5

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