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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.

Original publication

DOI

10.1161/01.ATV.0000115637.48689.77

Type

Journal article

Journal

Arterioscler Thromb Vasc Biol

Publication Date

03/2004

Volume

24

Pages

445 - 450

Keywords

Animals, Aorta, Aortic Diseases, Apolipoproteins E, Arteriosclerosis, Biopterin, Coenzymes, Crosses, Genetic, Cyclic GMP, Diet, Atherogenic, Endothelium, Vascular, GTP Cyclohydrolase, Humans, Hyperlipoproteinemia Type II, Hyperlipoproteinemia Type IV, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Nitric Oxide, Organ Specificity, Receptor, TIE-2, Recombinant Fusion Proteins, Superoxides, Vasodilation