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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:865.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Oral Administration of Tetrahydrobiopterin Slows the Progression of Atherosclerosis in Apolipoprotein E-Knockout Mice

Yoshiyuki Hattori; Sachiko Hattori; Xi Wang; Hiroko Satoh; Nobuo Nakanishi; Kikuo Kasai

From the Departments of Endocrinology & Metabolism (Y.H., S.H., X.W., H.S., K.K.), Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Biochemistry (N.N.), Meikai University School of Dentistry, Sakado, Saitama, Japan.

Correspondence to Yoshiyuki Hattori, MD, Department of Endocrinology & Metabolism, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. E-mail yhattori{at}dokkyomed.ac.jp

Objective— Although it has been reported that oral administration of tetrahydrobiopterin (BH4) prevents endothelial dysfunction and vascular oxidative stress in various rat models, the effect of treatment with BH4 on atherogenesis remains unclear.

Methods and Results— In this study, we investigated whether oral BH4 treatment might slow the progression of atherosclerosis using hypercholesterolemic apolipoprotein E-knockout mice. We report that ingesting BH4 in drinking water is sufficient to inhibit atherogenesis in mice. Furthermore, we report that BH4 treatment improves endothelial dysfunction and attenuates increased mRNA expression of NADPH oxidase components, as well as a number of inflammatory factors, such as LOX-1 and MCP-1, in the aortas of apolipoprotein E- knockout mice.

Conclusion— Strategies such as oral administration of BH4 to ensure continuous BH4 availability may be effective in restoring nitric oxide-mediated endothelial function and limiting vascular disease and the progression of atherosclerosis.

Although it has been reported that oral administration of tetrahydrobiopterin (BH4) prevents endothelial dysfunction and vascular oxidative stress in various rat models, the effect of treatment with BH4 on atherogenesis remains unclear. Strategies such as oral administration of BH4 to ensure continuous BH4 availability may be effective in restoring nitric oxide-mediated endothelial function and limiting vascular disease and the progression of atherosclerosis.

Key Words: apolipoprotein E-knockout mouse • atherosclerosis • endothelial function • tetrahydrobiopterin

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