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BASIC SCIENCE

Rescue of hypercholesterolemia-related impairment of angiogenesis by oral folate supplementation

Ken-ichiro Sasaki, MD^*, Junli Duan, MD^*, Toyoaki Murohara, MD^*,,*, Hisao Ikeda, MD^*, Satoshi Shintani, MD^*, Toshifumi Shimada, MD^*, Takako Akita, MD^*, Kimiyasu Egami, MD^* and Tsutomu Imaizumi, MD, FACC^*

^* Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Manuscript received September 10, 2002; revised manuscript received March 5, 2003, accepted March 20, 2003.

^* Reprint requests and correspondence: Dr. Toyoaki Murohara, Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550 Japan.
murohara{at}med.nagoya-u.ac.jp

OBJECTIVES: We examined whether oral folate supplementation would rescue a hypercholesterolemia (HC)-related impairment of ischemia-induced angiogenesis.

BACKGROUND: Folate protects against endothelial dysfunction, but the effect of folate supplementation on angiogenesis is little known.

METHODS: Sprague-Dawley rats were divided into four groups. Control rats were fed a normal diet (n = 18); HC rats (n = 18) were fed 2% cholesterol diet; and HC + folate (HC+F) rats were fed an HC diet with oral folate (0.003% in water). The left femoral artery and vein were surgically excised, and angiogenesis in the ischemic limb was evaluated. We also examined the effects of N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, on angiogenesis in the HC+F state.

RESULTS: Laser Doppler blood flow (LDBF) analysis showed lower ischemic/normal LDBF ratio in the HC group than in the control group. Angiographic and histologic analyses on day 14 revealed a smaller angiographic score (p < 0.001) and capillary density (p < 0.001) in the HC group than in controls, which were associated with reduced tissue NOx and cyclic guanosine monophosphate (cGMP) levels. The LDBF ratio, angiographic score, and capillary density were significantly restored in the HC+F group (p < 0.01 vs. HC), which were associated with increased serum folate and tissue NOx and cGMP levels. Finally, L-NAME treatment abolished the beneficial action of folate on angiogenesis in the HC state.

CONCLUSIONS: Ischemia-induced angiogenesis was inhibited by HC, which was rescued by oral folate supplementation, at least in part, via an NO-dependent manner.

Abbreviations and Acronyms   BH4   tetrahydrobiopterin   cGMP   cyclic guanosine monophosphate   eNOS   endothelial nitric oxide synthase   EDNO   endothelium-derived nitric oxide   HC   hypercholesterolemia   HC+F   hypercholesterolemia plus folate   LDBF   laser Doppler blood flow   L-NAME   N-nitro-L-arginine methyl ester   NO   nitric oxide   NOS   nitric oxide synthase   NOx   nitrate + nitrite

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