25 2 図 1. A B 図 2.ApoE ACh ApoE A SPER-NO NO ApoE B 7 nitric oxide: NO 8 NO endothelial NO synthase: enos 9 NO 10 NO 11 ApoE 12, 13 ApoE 14 ApoE C57BL

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1 新評議員要旨キーワード : 1.はじめに生活習慣病と動脈硬化 TEL: FAX : kazuo-y@juntendo.ac.jp 2 TIA 1A 3 4 1B 脂質異常症と脳動脈における血管内皮機能障害 6 129

生活習慣病と動脈硬化 113-8421 2-1-1 TEL: 03-3813-3111 FAX :

2 25 2 図 1. A B 図 2.ApoE ACh ApoE A SPER-NO NO ApoE B 7 nitric oxide: NO 8 NO endothelial NO synthase: enos 9 NO 10 NO 11 ApoE 12, 13 ApoE 14 ApoE C57BL/6J ACh 2A SPER-NO NO 2B 130

3 図 3.ApoE -1 ET-1 A ApoE ET-1 enos L-NAME B 図 4.Western blot ApoE enos enos ApoE enos A enos B ApoE -1 ET-1 3A ACh ET-1 ApoE 15, 16 enos ET-1 17 enos enos NO 20 enos enos NO 21, 22 ApoE enos enos 4A B NO NOx 5 enos enos NO ApoE 3 ACh 2A ET-1 enos L-NAME 131

ACh ET-1 ApoE 15, 16 enos ET-1 17 enos enos 18 19 NO 20 enos enos

4 25 2 図 5.ApoE NO nitrite nitrate NOx A ApoE NOx 3B enos 4A NOx 5 2 cyclic AMP/protein kinase A enos 23 enos NO enos 24 enos 4. 内臓脂肪と脳小血管病変 1998 American Heart Association ~30 31~ CT MRI cm cm 2 1 body mass index BMI BMI 40 5.おわりに enos 132

5 表 1. WMLs SLI Model 1 Model 2 OR (95%CI) P value OR (95%CI) P value WMLs Age 60 years 2.34 ( ) ( ) < VFA 100 cm ( ) ( ) 0.02 Large WC a 1.26 ( ) 0.44 Large WC b 1.41 ( ) 0.21 BMI 30 kg/m ( ) 0.92 BMI 25 kg/m ( ) 0.3 Hypertension 1.26 ( ) ( ) 0.42 SLI Age 60 years 2.17 ( ) < ( ) < VFA 100 cm ( ) ( ) 0.04 Large WC a 1.61 ( ) 0.09 Large WC b 1.73 ( ) 0.02 BMI 30 kg/m ( ) 0.68 BMI 25 kg/m ( ) 0.17 Hypertension 1.43 ( ) ( ) 0.18 OR, odds ratio; CI, confidence interval; VFA, visceral fat area; WC, waist circumference; BMI, body mass index; WMLs, white matter lesions; SLI, silent lacunar infarction. a 88 cm in women and 102 cm in men. b 90 cm in women and 85 cm in men VFA 100 cm 2 41 文献 1 Hata J, Ninomiya T, Hirakawa Y, Nagata M, Mukai N, Gotoh S, Fukuhara M, Ikeda F, Shikata K, Yoshida D, Yonemoto K, Kamouchi M, Kitazono T, Kiyohara Y: Secular trends in cardiovascular disease and its risk factors in Japanese: half-century data from the Hisayama Study ( ). Circulation 128: , Mannami T, Baba S, Ogata J: Strong and significant relationships between aggregation of major coronary risk factors and the acceleration of carotid atherosclerosis in the general population of a Japanese city: the Suita Study. Arch Intern Med 160: , Yamashiro K, Watanabe T, Tanaka R, Komine-Kobayashi M, Mizuno Y, Urabe T: Clustering of risk factors increases the incidence of echolucent carotid plaque in stroke patients. Cerebrovasc Dis 22: , Wolverson MK, Bashiti HM, Peterson GJ: Ultrasonic tissue characterization of atheromatous plaques using a high resolution real time scanner. Ultrasound Med Biol 9: , Ross R: Atherosclerosis an inflammatory disease. N Engl J Med 340: , Amarenco P, Labreuche J: Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 8: , Wolfrum S, Jensen KS, Liao JK: Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol 23: , Casino PR, Kilcoyne CM, Quyyumi AA, Hoeg JM, Panza JA: The role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients. Circulation 88: , Napoli C, de Nigris F, Williams-Ignarro S, Pignalosa O, Sica V, Ignarro LJ: Nitric oxide and atherosclerosis: an update. Nitric Oxide 15: , Maeda H, Matsumoto M, Handa N, Hougaku H, Ogawa S, Itoh T, Tsukamoto Y, Kamada T: Reactivity of cerebral blood flow to carbon dioxide in various types of ischemic cerebrovascular disease: evaluation by the transcranial 133

42 SLI Age 60 years 2.17 (1.47 3.20) <0.0001 2.33 (1.59 3.44) <0.0001 VFA 100 cm 2 1.70 (1.06 2.75) 0.03 1.69 (1.01 2.85) 0.04 Large WC a 1.61 (0.93 2.82) 0.09 Large WC b 1.73 (1.09 2.74) 0.

6 25 2 Doppler method. Stroke 24: , Rashid PA, Whitehurst A, Lawson N, Bath PM: Plasma nitric oxide (nitrate/nitrite) levels in acute stroke and their relationship with severity and outcome. J Stroke Cerebrovasc Dis 12: 82 87, Zhang SH, Reddick RL, Piedrahita JA, Maeda N: Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258: , Breslow JL: Mouse models of atherosclerosis. Science 272: , Yamashiro K, Milsom AB, Duchene J, Panayiotou C, Urabe T, Hattori N, Ahluwalia A: Alterations in nitric oxide and endothelin-1 bioactivity underlie cerebrovascular dysfunction in ApoE-deficient mice. J Cereb Blood Flow Metab 30: , d Uscio LV, Smith LA, Katusic ZS: Hypercholesterolemia impairs endothelium-dependent relaxations in common carotid arteries of apolipoprotein e-deficient mice. Stroke 32: , Maguire JJ, Wiley KE, Kuc RE, Stoneman VE, Bennett MR, Davenport AP: Endothelin-mediated vasoconstriction in early atherosclerosis is markedly increased in ApoE-/- mouse but prevented by atorvastatin. Exp Biol Med (Maywood) 231: , Lamping K, Faraci F: Enhanced vasoconstrictor responses in enos deficient mice. Nitric Oxide 8: , Liao JK, Shin WS, Lee WY, Clark SL: Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 270: , Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Lüscher T, Rabelink T: Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 99: 41 46, Huie RE, Padmaja S: The reaction of no with superoxide. Free Radic Res Commun 18: , Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM: Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399: , Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC: Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399: , Hashimoto A, Miyakoda G, Hirose Y, Mori T: Activation of endothelial nitric oxide synthase by cilostazol via a camp/protein kinase A- and phosphatidylinositol 3-kinase/Akt-dependent mechanism. Atherosclerosis 189: , Atochin DN, Wang A, Liu VW, Critchlow JD, Dantas AP, Looft-Wilson R, Murata T, Salomone S, Shin HK, Ayata C, Moskowitz MA, Michel T, Sessa WC, Huang PL: The phosphorylation state of enos modulates vascular reactivity and outcome of cerebral ischemia in vivo. J Clin Invest 117: , Eckel RH, Krauss RM: American Heart Association call to action: obesity as a major risk factor for coronary heart disease. AHA Nutrition Committee. Circulation 97: , Stevens GA, Singh GM, Lu Y, Danaei G, Lin JK, Finucane MM, Bahalim AN, McIntire RK, Gutierrez HR, Cowan M, Paciorek CJ, Farzadfar F, Riley L, Ezzati M; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index): National, regional, and global trends in adult overweight and obesity prevalences. Popul Health Metr 10: 22, Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, Lang CC, Rumboldt Z, Onen CL, Lisheng L, Tanomsup S, Wangai P, Razak F, Sharma AM, Anand SS; INTERHEART Study Investigators: Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 366: , Suk SH, Sacco RL, Boden-Albala B, Cheun JF, Pittman JG, Elkind MS, Paik MC; Northern Manhattan Stroke Study: Abdominal obesity and risk of ischemic stroke: the Northern Manhattan Stroke Study. Stroke 34: , Winter Y, Rohrmann S, Linseisen J, Lanczik O, Ringleb PA, Hebebrand J, Back T: Contribution of obesity and abdominal fat mass to risk of stroke and transient ischemic attacks. Stroke 39: , Bodenant M, Kuulasmaa K, Wagner A, Kee F, Palmieri L, Ferrario MM, Montaye M, Amouyel P, Dallongeville J; MORGAM Project: Measures of abdominal adiposity and the risk of stroke: the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) study. Stroke 42: , Park K, Yasuda N, Toyonaga S, Tsubosaki E, Nakabayashi H, Shimizu K: Significant associations of metabolic syndrome and its components with silent lacunar infarction in middle aged subjects. J Neurol Neurosurg Psychiatr 79: , Park K, Yasuda N, Toyonaga S, Yamada SM, Nakabayashi H, Nakasato M, Nakagomi T, Tsubosaki E, Shimizu K: Significant association between leukoaraiosis and metabolic syndrome in healthy subjects. Neurology 69: , Choi HS, Cho YM, Kang JH, Shin CS, Park KS, Lee HK: Cerebral white matter hyperintensity is mainly associated with hypertension among the components of metabolic syndrome in Koreans. Clin Endocrinol (Oxf) 71: , Bokura H, Yamaguchi S, Iijima K, Nagai A, Oguro H: 134

J Stroke Cerebrovasc Dis 12: 82 87, 2003 12 Zhang SH, Reddick RL, Piedrahita JA, Maeda N: Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.

7 Metabolic syndrome is associated with silent ischemic brain lesions. Stroke 39: , Fantuzzi G, Mazzone T: Adipose tissue and atherosclerosis: exploring the connection. Arterioscler Thromb Vasc Biol 27: , Examination Committee of Criteria for Obesity Disease in Japan; Japan Society for the Study of Obesity: New criteria for obesity disease in Japan. Circ J 66: , Yamashiro K, Tanaka R, Tanaka Y, Miyamoto N, Shimada Y, Ueno Y, Urabe T, Hattori N: Visceral fat accumulation is associated with cerebral small vessel disease. Eur J Neurol 21: , Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S: Adipokines: molecular links between obesity and atheroslcerosis. Am J Physiol Heart Circ Physiol 288: H , : , Park YW, Allison DB, Heymsfield SB, Gallagher D: Larger amounts of visceral adipose tissue in Asian Americans. Obes Res 9: , Kaufman FR: Type 2 diabetes mellitus in children and youth: a new epidemic. J Pediatr Endocrinol Metab 15 Suppl 2: , 2002 Abstract Lifestyle-related risk factors and cerebrovascular disease Kazuo Yamashiro Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan Recent changes in dietary habits and insufficient physical activity are associated with the increase of lifestyle-related risk factors such as dyslipidemia and obesity. Hypercholesterolemia is associated with endothelial dysfunction and reduced endothelial nitric oxide synthase phosphorylation in cerebral arteries. Furthermore, visceral fat accumulation is independently associates with the presence of cerebral small vessel disease. Visceral fat releases several bioactive mediators, such as adiponectin and inflammatory cytokines, that influence inflammation and coagulation, resulting in endothelial dysfunction and atherosclerosis. Because the prevalence of obesity in children and youth has increased, the role of lifestyle-related risk factors in cerebrovascular disease is expected to be more important in the future. Improvement of endothelial dysfunction caused by lifestyle-related risk factors could be one of the effective treatments for the prevention of cerebrovascular disease. Key words: lifestyle-related risk factors, nitric oxide, endothelial nitric oxide synthase, endothelial dysfunction 135

Circ J 66: 987 992, 2002 37 Yamashiro K, Tanaka R, Tanaka Y, Miyamoto N, Shimada Y, Ueno Y, Urabe T, Hattori N: Visceral fat accumulation is associated with cerebral small vessel disease.

研究成果報告書

研究成果報告書 21 4 25 peroxynitrite angiotensin II ETA MEK/ERK pathway endothelin-1 EDHF (EDHF) EDHF EDHF EDHF 2 [phosphodiesterase 3 (PDE3) cilostazol metformin thromboxane A2 ozagrel eicosapentaenoic acid (EPA) angiotensin