Journal article

Dihydrofolate reductase protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency.

Abstract:: Tetrahydrobiopterin (BH4) is a required cofactor for the synthesis of NO by endothelial nitric oxide synthase (eNOS), and endothelial BH4 bioavailability is a critical factor in regulating the balance between NO and superoxide production (eNOS coupling). Biosynthesis of BH4 is determined by the activity of GTP-cyclohydrolase I (GTPCH). However, BH4 levels may also be influenced by oxidation, forming 7,8-dihydrobiopterin (BH2), which promotes eNOS uncoupling. Conversely, dihydrofolate reductase (DHFR) can regenerate BH4 from BH2, but whether DHFR is functionally important in maintaining eNOS coupling remains unclear. To investigate the mechanism by which DHFR might regulate eNOS coupling in vivo, we treated wild-type, BH4-deficient (hph-1), and GTPCH-overexpressing (GCH-Tg) mice with methotrexate (MTX), to inhibit BH4 recycling by DHFR. MTX treatment resulted in a striking elevation in BH2 and a decreased BH4:BH2 ratio in the aortas of wild-type mice. These effects were magnified in hph-1 but diminished in GCH-Tg mice. Attenuated eNOS activity was observed in MTX-treated hph-1 but not wild-type or GCH-Tg mouse lung, suggesting that inhibition of DHFR in BH4-deficient states leads to eNOS uncoupling. Taken together, these data reveal a key role for DHFR in regulating the BH4 vs BH2 ratio and eNOS coupling under conditions of low total biopterin availability in vivo.

Publication status:: Published

Actions

Email

Email this record

Send the bibliographic details of this record to your email address.

Your Email
Please enter the email address that the record information will be sent to.

-
Your message (optional)
Please add any additional information to be included within the email.
Share
Cite

Cite this record

APA Style

Crabtree, M., Hale, A. B., & Channon, K. (2011). Dihydrofolate reductase protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency. Free Radical Biology and Medicine, 50(11), 1639–1646.

MLA Style

Crabtree, M, et al. “Dihydrofolate Reductase Protects Endothelial Nitric Oxide Synthase from Uncoupling in Tetrahydrobiopterin Deficiency.” Free Radical Biology and Medicine, vol. 50, no. 11, 2011, pp. 1639–46.

Chicago Style

Crabtree, M, AB Hale, and K Channon. 2011. “Dihydrofolate Reductase Protects Endothelial Nitric Oxide Synthase from Uncoupling in Tetrahydrobiopterin Deficiency.” Free Radical Biology and Medicine 50 (11): 1639–46.
Print

Access Document

Publisher copy:: 10.1016/j.freeradbiomed.2011.03.010

Authors

+ Crabtree, M More by this author

Role:: Author

+ Hale, AB More by this author

Role:: Author

+ Channon, K More by this author

Institution:: University of Oxford
Division:: MSD
Department:: RDM
Sub department:: RDM Cardiovascular Medicine
Role:: Author

Journal:: Free radical biology and medicine More from this journal
Volume:: 50
Issue:: 11
Pages:: 1639-1646
Publication date:: 2011-06-01
DOI:: 10.1016/j.freeradbiomed.2011.03.010
EISSN:: 1873-4596
ISSN:: 0891-5849

Language:: English
Keywords:: Transgenes

Animals

Methotrexate

Mice, Knockout

Mice

Tetrahydrofolate Dehydrogenase

Mice, Transgenic

Endothelium

Mice, Inbred C57BL

RNA, Small Interfering

Biopterin

Nitric Oxide Synthase

Oxidative Coupling

Oxidation-Reduction
Pubs id:: pubs:124359
UUID:: uuid:1f4a410d-4061-491e-bc7f-6d874750c0db
Local pid:: pubs:124359
Source identifiers:: 124359
Deposit date:: 2012-12-19
ARK identifier:: ark:/29072/ora_1f4a410d4061491ebc7f6d874750c0db

Terms of use

Copyright date:: 2011

Licence:: Terms and Conditions of Use for Oxford University Research Archive

Views and Downloads

Views and downloads will return soon

If you are the owner of this record, you can report an update to it here: Report update to this record

TO TOP