title: Short- and long-term treatment with folic acid suppresses thrombus formation in atherogenic mice in vivo.
abstract: In the present study, we examined the effects of short- and long-term treatment with folic acid (FA) on thrombus formation in vivo in atherogenic mice to explore a novel agent for the prevention of atherothrombotic disease. Apolipoprotein E and low-density lipoprotein receptor double deficient (ApoE(-/-)LDLR(-/-)) mice were orally administrated a single bolus of FA (20mg/kg) or fed an atherogenic diet with or without FA (0.02, 0.5, and 1.5mg/kg) for 12 weeks. Thrombus formation and endothelial function were assessed in vivo using the He-Ne laser-induced carotid artery thrombus formation test and the flow-mediated vasodilation method. Platelet reactivity was assessed ex vivo using haemostatometry. Short-term treatment with FA markedly increased plasma folate levels and significantly suppressed laser-induced thrombus formation in apoE(-/-)LDLR(-/-) mice. Short-term treatment with FA suppressed platelet reactivity in apoE(-/-)LDLR(-/-) mice, but FA treatment did not affect endothelial function or plasma homocysteine levels. Long-term treatment with FA increased plasma folate levels dose-dependently. Thrombus formation and endothelial dysfunction were suppressed by treatment with 0.5 and 1.5mg/kg of FA, respectively, but not with 0.02mg/kg of FA, whereas platelet reactivity was not altered by treatment with any dose of FA. Long-term treatment with all doses of FA decreased the plasma homocysteine levels in apoE(-/-)LDLR(-/-) mice, although this result was not consistent with its anti-thrombotic action. In conclusion, our data showed that short- and long-term treatment with FA could suppress in vivo thrombus formation in an atherogenic setting, independent of its hypohomocysteinemic action.
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, 589-8511, Japan. Electronic address: ytamura@med.kindai.ac.jp.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University, 518 Arise, Igawadani-cho, Nishi-ku, Kobe, 651-2180, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Department of Health and Nutrition, Faculty of Liberal Arts, Osaka Shoin Women's University, 4-2-26 Hishiya-nishi, Higashi-Osaka, 577-8550, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ijiri
authors.affiliation: Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University, 518 Arise, Igawadani-cho, Nishi-ku, Kobe, 651-2180, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Naemura
authors.affiliation: Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University, 518 Arise, Igawadani-cho, Nishi-ku, Kobe, 651-2180, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Yamamoto
keywords: Atherothrombosis; Endothelial function; Folic acid; Platelet activation