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

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.

• Authors: Nicholas J Alp, Martina A McAteer, Jeffrey Khoo, Robin P Choudhury, Keith M Channon
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 24 Issue 3 Pg. 445-50 (Mar 2004) ISSN: 1524-4636 [Electronic] United States
• PMID: 14707037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Coenzymes
• Recombinant Fusion Proteins
• Superoxides
• Biopterin
• Nitric Oxide
• Receptor, TIE-2
• GTP Cyclohydrolase
• sapropterin
• Cyclic GMP

Topics

• Animals
• Aorta (metabolism)
• Aortic Diseases (metabolism, physiopathology)
• Apolipoproteins E (deficiency, genetics)
• Arteriosclerosis (metabolism, physiopathology)
• Biopterin (analogs & derivatives, biosynthesis, physiology)
• Coenzymes (biosynthesis, physiology)
• Crosses, Genetic
• Cyclic GMP (metabolism)
• Diet, Atherogenic
• Endothelium, Vascular (metabolism, physiopathology)
• GTP Cyclohydrolase (biosynthesis, genetics, physiology)
• Humans
• Hyperlipoproteinemia Type II (complications, genetics)
• Hyperlipoproteinemia Type IV (complications, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Nitric Oxide (biosynthesis)
• Organ Specificity
• Receptor, TIE-2 (genetics)
• Recombinant Fusion Proteins (biosynthesis, physiology)
• Superoxides (metabolism)
• Vasodilation (physiology)