Hidetoshi Kawashima, Yoshikage Nakajima, Yoshio Matubara, Junichi Nakanowatari,
Taneo Fukuta, Saburo Mizuno, Sumiko Takahashi, Tetsuya Tajima and Tetsuya
Nakamura
Pharmacological Evaluation Section, Tokyo Research Laboratories, Eisai
Co., Ltd., Koishikawa 4-chome, Bunkyo-ku, Tokyo 112-88, Japan
Abstract: Gamma-Carboxyglutamic acid (Gla)-containing protein,
synthesized in the presence of vitamin K, has been found in atherogenic
plaques, but the pharmacological effect of vitamin K on atherosclerosis
is unclear. We examined whether vitamin K2 (menatetrenone) could affect
the progression of both atherosclerosis and hypercoagulability in hypercholesterolemic
rabbits. Vitamin K2 in daily doses of 1, 10 and 100 mg/kg was given with
a 0.5% cholesterol diet for 10 weeks to 8 rabbits each. The plasma levels
of total-cholesterol in the vitamin K2-treated groups were clearly lower
than that of the hypercholesterolemic control group. The excessive dose
of vitamin K2, even at the high dose of 100 mg/kg/day for 10 weeks, did
not accelerate the progression of atherosclerosis and did not promote the
coagulative tendency in the rabbits. In contrast, the vitamin K2 treatment
(1 to 10 mg/kg/day) suppressed the progression of atherosclerotic plaques,
intima-thickening and pulmonary atherosclerosis, the increase of ester-cholesterol
deposition in the aorta, and both the elevation in plasma factor X level
and increase in Hepaplastin(R)test value in the rabbits. These results indicate
that the pharmacological dose of vitamin K2 prevents both the progression
of atherosclerosis and the coagulative tendency by reducing the total-cholesterol,
lipid peroxidation and factor X activity in plasma, and the ester-cholesterol
deposition in the aorta in hypercholesterolemic rabbits.
Keywords: Vitamin K2 (menatetrenone), Hypercholesterolemia, Atherosclerosis,
Blood coagulation, Factor X