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Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice
Open accessAbstract
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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“Overexpression of GCH1 in cells and mouse models improves eNOS function (19, 143).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [19]
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Metadata
- 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
- bronze
- doi.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- British Heart Foundation
- Topics
- Health Sciences › Medicine › Physiology (medical) › 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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