Cited by 194Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionAtherosclerosis and Cardiovascular Diseases

Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice

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Alp, Nicholas J., McAteer, Martina A., Khoo, Jeffrey, Choudhury, Robin P., Channon, Keith M.·2004·Arteriosclerosis, Thrombosis, and Vascular Biology

Abstract

Objective— Increased production of reactive oxygen species and loss of endothelial nitric oxide (NO) bioactivity are key features of vascular disease states such as atherosclerosis. Tetrahydrobiopterin (BH4) is a required cofactor for NO synthesis by endothelial nitric oxide synthase (eNOS); pharmacologic studies suggest that reduced BH4 availability may be an important mediator of endothelial dysfunction in atherosclerosis. We aimed to investigate the importance of endothelial BH4 availability in atherosclerosis using a transgenic mouse model with endothelial-targeted overexpression of the rate-limiting enzyme in BH4 synthesis, GTP-cyclohydrolase I (GTPCH). Methods and Results— Transgenic mice were crossed into an ApoE knockout (ApoE-KO) background and fed a high-fat diet for 16 weeks. Compared with ApoE-KO controls, transgenic mice (ApoE-KO/GCH-Tg) had higher aortic BH4 levels, reduced endothelial superoxide production and eNOS uncoupling, increased cGMP levels, and preserved NO-mediated endothelium dependent vasorelaxations. Furthermore, aortic root atherosclerotic plaque was significantly reduced in ApoE-KO/GCH-Tg mice compared with ApoE-KO controls. Conclusions— These findings indicate that BH4 availability is a critical determinant of eNOS regulation in atherosclerosis and is a rational therapeutic target to restore NO-mediated endothelial function and reduce disease progression.

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Authors
Alp, N. J., McAteer, M. A., Khoo, J., Choudhury, R. P., & Channon, K. M.
Affiliations
John Radcliffe Hospital (GB)
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Published
2004-03
Volume
24
Issue
3
Pages
445-450
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
OpenAlex
W2172004618
Cited by
194
References
34
Citations by year
2025: 5 · 2024: 1 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 11 · 2016: 7 · 2015: 4 · 2014: 17 · 2013: 10 · 2012: 13
FWCI
8.55
Type
journal article
Language
en
Open access
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust
  • British Heart Foundation
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Keywords
tetrahydrobiopterin, GTP cyclohydrolase I, endothelial dysfunction, atherosclerosis, endothelial nitric oxide synthase, nitric oxide bioactivity, eNOS uncoupling, superoxide production, cGMP signaling, ApoE-deficient mice, high-fat diet, aortic plaque, transgenic mice
MeSH terms
Animals, Aorta, Aortic Diseases, Apolipoproteins E, Arteriosclerosis, Biopterins, Coenzymes, Crosses, Genetic, Diet, Atherogenic, Endothelium, Vascular, GTP Cyclohydrolase, Cyclic GMP, Humans, Hyperlipoproteinemia Type II, Hyperlipoproteinemia Type IV, Mice, Inbred C57BL, Mice, Transgenic, Nitric Oxide, Organ Specificity, Recombinant Fusion Proteins, Superoxides, Vasodilation, Mice, Knockout, Receptor, TIE-2, Mice

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