井尻 吉信

Introduction: Moderate and regular consumption of wine reduces the risk of acute coronary thrombotic events. The mechanism of the anti-thrombotic effect of wine is not clear. Extract or purified ingredients of grapes have not yet been studied for anti-thrombotic effect. Materials and methods: Anti-thrombotic effect of proanthocyanidin, a highly purified ingredient of grape seed, was assessed by,a shear-induced thrombosis test in vitro and by a laser-induced thrombosis test in the mouse carotid artery, in vivo. Results and conclusions. Intravenously (20 mg/kg body weight, BW) or orally (2x200 mg/kg BW) administered proanthocyanidin significantly inhibited the Laser-irradiation induced thrombus formation in the carotid artery (both P=0.01). Subsequent to oral administration of proanthocyanidin, in vitro platelet reactivity to shear stress has been inhibited. The latter suggests that the in vivo anti-thrombotic effect of proanthocyanidin may be due to a direct inhibitory effect on platelets. (C) 2004 Elsevier Ltd. All rights reserved.

Resveratrol is one of the major polyphenolics in red wine that has been shown to exert the preventive effects against cardiovascular diseases. The effect of trans-resveratrol (t-RES) administered as an ingredient of the diet on the atherothrombotic tendency was assessed in genetically hypercholesterolemic mice after laser-induced damage on endothelium. Mice lacking both apolipoprotein E and low-density lipoprotein receptor (apoE-/-/LDLR-/-) were fed with a high-fat diet with or without t-RES (9.6 and 96 mg/kg diet) for 8 weeks. The atherosclerotic tendency was morphometrically analyzed in their aortae. The thrombotic tendency was determined by inducing thrombus by the irradiation of a helium-neon laser on carotid arteries of these mice with injection of Evans blue. Atherosclerotic area and thrombus size were evaluated by image analyzing in a computer system. Even though the plasma concentrations of lipids (total cholesterol and triacylglycerol) did not change in the control and t-RES groups, a significant decrease (approximately 30%) in the formation of atheroma was observed in the aortae of the t-RES group. The size of laser-induced thrombus that mostly consisted of platelet aggregates was significantly reduced (approximately 25%) in the t-RES group compared with that in the control group. Thus, t-RES orally administrated with a high-fat diet in apoE-/-/LDLR-/- mice significantly suppressed atherosclerosis in their aortae and reduced the laser-induced thrombosis in their carotid arteries.

赤ワインに多く含まれるトランスリスベラトロールの作用が注目されている。そこで、先天的動脈硬化発症ApoE-/- LDLR-/- ダブルノックアウトマウスの頸動脈とHe-Neレーザー惹起血栓形成法を組み合わせた、食餌感受性の高い血栓のマウスモデルを用い、トランスリスベラトロールの有用性を検討した。その結果、トランスリスベラトロールは強い抗血栓作用ならびに抗動脈硬化作用を有していることが明らかとなった。本論文は臨床栄養学（食事による循環器疾患の予防）領域の業績である。担当部分：全般

The prevention of arterial thrombotic diseases has a high priority in developed countries. An inappropriate diet may be an important risk factor for thrombotic events. The daily intake of an anti-thrombotic diet may offer a convenient and effective way of prevention. The aim of the present study was to test tomato extracts for anti-thrombotic effects and to identify those varieties that have such an effect. A shear-induced platelet-function test (haemostatometry) was used to test anti-thrombotic potential in vitro. Extracts from those tomato varieties that showed a significant anti-thrombotic activity in vitro were further assessed in vivo, using a laser-induced thrombosis test in mice. One tomato variety (KG99-4) showed significant anti-thrombotic activity both in vitro and in vivo. KG99-4 inhibited not only platelet-rich thrombus formation but also had a thrombolytic effect. It is concluded that haemostatometry can detect and classify the anti-thrombotic potential of fruits and vegetables and offers a simple way of screening for such effects.

Atherothrombosis can be regarded as a 'life-style related disease' of which diet is one of the important risk factors. The prophylactic effect of partially defatted flaxseed meal (PDFM) on atherothrombosis has not yet been studied. The aim of this study was to assess the effect of PDFM and a lignan from flaxseed, secoisolariciresinol diglucoside (SDG), on thrombosis and atherogenesis. An earlier developed test, the quantitative assessment of laser-induced thrombus formation in the carotid artery of apolipoprotein E and low-density lipoprotein receptor deficient mice was used in this study. Thrombotic and atherosclerotic status was assessed in mice kept on a high-fat diet for 8 weeks (40% in energy). The diet contained 0.05% cholesterol alone (control) or the same cholesterol with added PDFM (5% w/w; 8.3 g/kg body weight per day) or SDG (0.06% w/w; 100 mg/kg body weight per day). PDFM showed antithrombotic (P < 0.01) and anti-atherogenic effect (P < 0.01). SDG did not affect either atherogenesis or thrombosis. This study suggests that dietary intake of PDFM can be beneficial in reducing the risk of high-fat-induced atherothrombosis. (C) 2003 Lippincott Williams Wilkins.

イソフラボンアグリコンならびにイソフラボングルコシドが血栓形成傾向に及ぼす影響を明らかにするため実験を行った。その結果、イソフラボンアグリコンは高脂肪食による易血栓傾向を有意に抑制した。一方、イソフラボングルコシドにはその効果が認められなかった。この血栓形成抑制効果は血小板反応性の阻害による可能性が示唆された。本論文は臨床栄養学（食事による循環器疾患の予防）領域の業績である。担当部分：全般

末梢の閉塞性動脈硬化症（足の血管の動脈硬化がすすみ、血管が細くなったり、つまったりして、充分な血流が保てなくなる病気）に対する診断法の中でも無侵襲的に検査が可能な超音波法を応用した。とくに、カラードプラー法による検査は、血行動態の微細な変化が抽出され、かなり詳細な病態が把握され、治療手段の良い指針となった。今後さらに本法の有用性を明らかにしていきたいと考えている。本論文は血液生理学領域の業績である。担当部分：共同研究につき抽出不可能

Epidemiological studies suggest the high fat content of the Western diet to be responsible for atherosclerosis and its thrombotic complications. Despite such a prevailing view, few animal experiments have so far succeeded in demonstrating enhanced thrombogenicity due to a high fat diet. Even a high fat and a very high cholesterol (1%) diet has failed to demonstrate an enhanced thrombotic reaction in rodents and rabbits. The aim of the present study was twofold. First, we wanted to establish a new, sensitive and specific in vivo thrombosis model in mice, which can then be used to study the effect of diets. Second, we intended to employ such a thrombosis model in investigations into the effect of high or low fat diets on thrombosis. The technique described uses 'a laser to induce thrombus formation in the exposed carotid artery of apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice. Thrombus formation was recorded on video, analysed by computer, and the size of thrombus was calculated by image analysis software. Thrombotic status was evaluated by analysing a total of 61 individual images of the thrombotic reaction, which were taken over 600 s. The severity of atherosclerosis was assessed by image analysis of the stained elastic fibers. Two kinds of diets were used. the Western type, high fat diet contained 20% fat (w/w) and 0.05% cholesterol (w/w); the low fat diet contained 7% fat, without cholesterol. These diets were on the basis of AIN93G and were given to mice for 4 or 8 weeks. The high fat diet significantly enhanced both the thrombotic reaction and the development of atherosclerosis as compared with the low fat diet. (C) 2002 Lippincott Williams Wilkins.

心筋梗塞や脳梗塞などの血栓性疾患を食事で予防することは極めて重要な課題である。それ故、食餌の影響を捉えることができる動物モデルの開発が求められていた。そこで我々は、先天的動脈硬化発症ApoE-/- LDLR-/- ダブルノックアウトマウスの頸動脈とHe-Neレーザー惹起血栓形成法を組合すことにより、食餌感受性の高い血栓のマウスモデルを確立した。さらに、高脂肪食は血栓形成傾向及び動脈硬化度を有意に増大させた。また日本人が日常摂取する量のイソフラボンアグリコンは、高脂肪食による血栓形成傾向の亢進を抑制した。本論文は臨床栄養学（食事による循環器疾患の予防）領域の業績である。担当部分：全般