Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP-cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in ApoE-knockout mice.
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).


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.
Alp
Nicholas J
NJ
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
McAteer
Martina A
MA
Khoo
Jeffrey
J
Choudhury
Robin P
RP
Channon
Keith M
KM
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001018:Aortic Diseases / Q000378:metabolism / Q000503:physiopathology*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism / Q000503:physiopathology*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000502:physiology; D003067:Coenzymes / Q000096:biosynthesis* / Q000502:physiology; D003433:Crosses, Genetic; D006152:Cyclic GMP / Q000378:metabolism; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D006136:GTP Cyclohydrolase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000235:genetics; D006953:Hyperlipoproteinemia Type IV / Q000150:complications / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis; D009928:Organ Specificity; D042787:Receptor, TIE-2 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology
D001057:Apolipoproteins E; D003067:Coenzymes; D011993:Recombinant Fusion Proteins; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D042787:Receptor, TIE-2; D006136:GTP Cyclohydrolase; C003402:sapropterin; D006152:Cyclic GMP