on January 5, 2004
Arteriosclerosis, Thrombosis, and Vascular Biology. 2004
Published online before print January 5, 2004, doi: 10.1161/01.ATV.0000115637.48689.77
Published online before print January 5, 2004, doi: 10.1161/01.ATV.0000115637.48689.77
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Submitted on September 26, 2003
Accepted on December 19, 2003
Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice
Nicholas J. Alp ;
From the Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
* To whom correspondence should be addressed. E-mail: keith.channon{at}cardiov.ox.ac.uk.
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.
Key words: nitric oxide synthase • endothelium • atherosclerosis • hypercholesterolemia
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