1997 년도산학협동연구비수혜논문 Korean Circulation J 2000;30 4 : ApoE Knockout Mouse 에서원발성동맥경화부위의 혈관협착부위가동맥경화억제약물의투여시미치는 영향 - 혈관재구도의관점에서본변화 서홍석 이은미 안정천 황인희

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1 1997 년도산학협동연구비수혜논문 Korean Circulation J 2000;304: ApoE Knockout Mouse 에서원발성동맥경화부위의 혈관협착부위가동맥경화억제약물의투여시미치는 영향 - 혈관재구도의관점에서본변화 서홍석 이은미 안정천 황인희 황교승 송우혁임도선 박창규 김영훈 심완주 오동주 노영무 The Effects of Antiproliferative Drugs at Stenotic Area Associated with Primary Atherosclerotic Lesions in ApoE Knockout Mouse-Change of Vascular Remodeling Hong Seog Seo, MD, Eun Mi Lee, MD, Jeong Cheon Ahn, MD, Soo Mi Kim, MD, Hwang In Hee, MD, Kyo Seung Hwang, MD, Woo Hyuk Song, MD, Do Sun Lim, DM, Chang Gyu Park, MD, Young Hoon Kim, MD, Wan Joo Shim, MD, Dong Joo Oh, MD and Young Moo Ro, MD Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea ABSTRACT Apolipoprotein apo E deficient mouse can produce reproducible fixed stenotic primary atherosclerotic lesion, which reveals failure to remodel of vascular lumen, in the ascending aorta, external carotid, common carotid, iliac, femoral and popliteal arteries. To evaluate the effect of drugs in regarding to both prevention of primary atherosclerotic lesion and vascular remodeling, a systematic analysis of distribution of atherosclerotic lesions was undertaken in chow-fed, 9-momth-old apo E deficient mice, which was administrated drugs including asprin, methotrexate, probucol, sulodexide, diltiazem, cilazapril, trimetazidine, molsidomine, pentoxiphylline and Ginexin for 7 month from 3 month-old. On gross and microscopic examination, formation of primary atheroscleotic lesions could be delated and/or prevented patially by effets of these drugs. On morphometric examination, failure to remodel forming vascular stenosis could not be seen, though relatively mild atherosclerotic lesion occured at vascular tree. These data suggest that the stenotic process in advanced atherosclerotic vessels can be delayed and/or prevented by several drugs including methotrexate, probucol, sulodexide, diltiazem, cilazapril, trimetazidine, molsidomine, pentoxiphylline and Ginexin in vivo state. Korean Circulation J 2000;304: KEY WORDSApolipoprotein E deficient mouse Atherosclerosis Vascular remodel Primary prevention. 서 론 517

2 518 연구방법 Korean Circulation J 2000;304:

3 결 과 쥐의체중비교와혈중 lipid profile 의비교 Table 1. Plasma lipid levels of 9-month-old apoe-deficient and wild type mice 육안적동맥경화병소의비교 병변의조직학적비교 Mouse Cholesterol mg/dl Triglyceride md/dl Wild type C57/B Control apoe / ApoE /asprin ApoE/methotrexate ApoE/probucol ApoE/sulodexide ApoE/diltiazem ApoE/cilazapril ApoE/molsidomine ApoE/trimetazidine ApoE/pentoxiphyline

4 Table 2. Distribution and severity of peripheral atherosclerotic lesions by dissecting microscope in 9-month-old apoe-deficient mice according to drug administration ApoE ECA score CCA score AA score AR score IT score FA score PA score Sum of score ApoE /control ApoE /asprin ApoE /methotrexate ApoE /probucol ApoE /sulodexide ApoE /diltiazem ApoE /cilazapril Korean Circulation J 2000;304:

5 Table 2. Continued ApoE ECA score CCA score AA score AR score IT score FA score PA score Sum of score ApoE /molsidomine ApoE /trimetazidine ApoE /pentoxiphyline Score 0, normal1, fluffy edge not well defined2, edge well defined, cream color, usually oval or round3, hard to touch, pearly looking, concentric. Score represents mean value of left and right side. EC=external carotid arterycc=common carotid arteryaa=aortic archar=aorta at the level of kidney, IT=iliac trifurcation arteryfa=femoral arterypa=popliteal artery Table 3. 죽상경맥경화병변의조직학적관찰을비교하여본바죽상반형성의빈도 Mouse ECA CCA AA AR IA FA PA Total % Control 12/12 12/12 6/6 3/6 12/12 12/12 12/12 69/ Aspirin 2/ 5 0/ 2 3/3 1/2 0/ 6 0/ 6 1/ 6 7/ Methotrexate 0/ 9 4/10 6/6 3/6 1/11 0/11 0/ 7 14/ Probucol 1/ 7 1/ 8 5/5 4/5 0/ 8 0/ 8 0/ 6 11/ Sulodexide 0/12 2/12 6/6 4/6 0/ 8 0/10 0/ 4 12/ Dilitiazem1 1/12 1/12 5/6 1/6 1/11 0/11 0/10 9/ Cilazapril 0/12 0/ 9 6/6 4/6 1/11 0/10 0/ 7 11/ Molsidomine 6/11 1/10 6/6 4/6 1/11 0/12 0/11 18/ Trimetazidine 3/ 7 2/10 5/5 2/5 1/10 0/12 0/11 12/ Pentoxiphyline 0/12 1/ 6 5/6 2/5 2/10 0/12 0/ 8 10/ GNX 1/ 8 3/ 8 5/5 3/5 0/10 1/ 8 1/ 8 14/ EC=external carotid arterycc=common carotid arteryaa=aortic achar=aorta at the level of kidney IT=iliac trifurcation arteryfa=femoral arterypa=popliteal artery 521

6 Table 4. Extracellular cholesterol의 deposition (cholesterol cleft) 의빈도 Mouse ECA CCA AA AR IA FA PA Total % Control 12/12 12/12 6/6 3/6 12/12 12/12 12/12 69/ Aspirin 1/ 5 1/ 2 1/3 0/2 0/ 6 0/ 6 0/ 6 3/ Methotrexate 0/ 9 2/10 6/6 1/6 0/11 0/11 0/ 7 9/ Probucol 0/ 7 1/ 8 2/5 1/5 0/ 8 0/ 8 0/ 6 4/ Sulodexide 0/12 2/12 6/6 1/6 0/ 8 0/10 0/ 4 7/ Dilitiazem1 1/12 1/12 3/6 0/6 1/11 0/11 0/10 6/ Cilazapril 0/12 0/ 9 2/6 2/6 0/11 0/10 0/ 7 4/ Molsidomine 1/11 0/10 3/6 2/6 0/11 0/12 0/11 6/ Trimetazidine 0/ 7 1/10 2/5 1/5 0/10 0/12 0/11 4/ Pentoxiphyline 0/12 0/ 6 3/6 0/5 0/10 0/12 0/ 8 3/ GNX 1/ 8 2/ 8 4/5 3/5 0/10 0/ 8 0/ 8 10/ EC=external carotid arterycc=common carotid arteryaa=aortic achar=aorta at the level of kidney IT=iliac trifurcation arteryfa=femoral arterypa=popliteal artery Table 5. Smooth muscle cell layer 의 destruction Mouse ECA CCA AA AR IA FA PA Total % Control 12/12 12/12 3/3 3/6 12/12 12/12 12/12 69/ Aspirin 2/ 5 0/ 2 2/3 0/2 0/ 6 0/ 6 0/ 6 4/ Methotrexate 0/ 9 1/10 5/6 4/6 2/11 0/11 0/ 7 12/ Probucol 1/ 7 2/ 8 3/5 1/5 0/ 8 1/ 8 0/ 6 8/ Sulodexide 1/12 2/12 4/6 4/6 0/ 8 0/10 0/ 4 11/ Dilitiazem1 1/12 0/12 1/6 1/6 1/11 0/11 0/10 4/ Cilazapril 0/12 0/ 9 6/6 0/6 0/11 0/10 0/ 7 6/ Molsidomine 3/11 0/10 3/6 2/6 2/11 2/12 0/11 12/ Trimetazidine 1/ 7 2/10 4/5 2/5 1/10 1/12 0/11 11/ Pentoxiphyline 0/12 0/ 6 1/6 1/5 0/10 0/12 0/ 8 2/ GNX 1/ 8 1/ 8 0/5 1/5 0/10 1/ 8 0/ 8 5/ EC=external carotid arterycc=common carotid arteryaa=aortic achar=aorta at the level of kidney IT=iliac trifurcation arteryfa=femoral arterypa=popliteal artery Table 6. Adventititial inflammatory cell infiltration의빈도 Mouse ECA CCA AA AR IA FA PA Total % Control 12/12 12/12 3/3 3/6 12/12 12/12 12/12 69/ Aspirin 1/ 5 1/ 2 1/3 2/2 0/ 6 0/ 6 0/ 6 5/ Methotrexate 0/ 9 1/10 5/6 4/6 2/11 0/11 0/ 7 12/ Probucol 1/ 7 2/ 8 3/5 1/5 0/ 8 1/ 8 0/ 6 8/ Sulodexide 1/12 1/12 4/6 3/6 0/ 8 1/10 0/ 4 10/ Dilitiazem1 1/12 0/12 1/6 1/6 1/11 0/11 0/10 4/ Cilazapril 0/12 0/ 9 4/6 1/6 1/11 1/10 0/ 7 7/ Molsidomine 3/11 0/10 3/6 2/6 2/11 2/12 0/11 12/ Trimetazidine 1/ 7 2/10 4/5 2/5 1/10 1/12 0/11 11/ Pentoxiphyline 0/12 0/ 6 3/6 2/5 1/10 0/12 0/ 8 6/ GNX 0/ 8 1/ 8 5/5 3/5 0/10 1/ 8 1/ 8 11/ EC=external carotid arterycc=common carotid arteryaa=aortic achar=aorta at the level of kidney IT=iliac trifurcation arteryfa=femoral arterypa=popliteal artery 522 Korean Circulation J 2000;304:

7 Fig. 1. Relation of plaque size and lumen size in drug-administrated apo E deficient mice from morphometric data shows positive vascular remodeling occured. Fig. 2. Relation of plaque size and medial area in drug-administrated apo E deficient mice from morphometric data shows preversed vascular remodeling. Morphometric evaluation의비교 고찰 523

8 524 Korean Circulation J 2000;304:

9 본연구의한계점 : 연구배경 : 요약 방법 : 결과 : 525

10 결론 : 526 중심단어 감사문 REFERENCES 1) Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Eng J Med ) Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, Wong C, et al. Arterial remodeling after coronary angioplasty A serial intravascular ultrasound study. Circulation ) Rapacz J, Hasler-Rapacz J, Taylor KM, Checovich WJ, Attie AD. Lipoprotein mutations in pigs are associated with elevated plasma cholesterol and atherosclerosis. Science ) Seo HS, Lombard DM, Polinsky P, Powell-Braxton L, Bunting S, Schwart SM, et al. Peripheral vascular stenosis in Apolipoprotein E-deficient mice. Potential roles of lipid deposition, medial atrophy, and adventitial inflammation ) Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W, Rosenfeld ME, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. Circulation Korean Circulation J 2000;304:

11 ) Cheng GC, Loree HM, Kamm RD, Fishben MC, Lee RT. Distribution of circumferential stress in ruptured and stable atherosclerotic leions. A structural analysis with histopathological correlation. Circulation ) Nakashima Y, Plump As, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb ) Clarkson TB, Prichard RW, Morgan TM, Petrick GS, Klein KP. Remodeling of coronary arteries in human and nonhuman primates. JAMA ) Cronstein BN. Molecular therapeutics. Methorexate and its mechanism of action. Arthritis & Rheumatism ) Steinberg D. Studies in the mechanism of action of probucol. Am J Cardiol H-21H. 11) Teien AN, Abildgaard U, Hook M. The anticogulant effect of heparan sulfate and dermatan sulfate. Thromb Res ) Tiozzo R, Cingi MR, Pietrangelo A, Albertazzi L, Calandra S, Milana MR. Effect of heparin-like compounds on the in vitro proliferation and protein synthesis of various cell types. Arzneim-Forsch/Drug Res ) Guarneri C, Muscari C. Effect of trimetazidine on mitochondrial function and oxidative damage during reperfusion of ischemic hypertrophied rat myocardium. Pharmacology ) Kukovetz WR. Mecahism of vasodilation by molsidomine. Am Heart J ) Ollivier V, Houssaye S, Ternisien C. Endotoxin-induced tissue factor mrna in human monocytes is negatively regulated by cyclic AMP-dependent mechanism. Blood ) Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Buller HR, et al. Inhibition of endotoxininduced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest ) Smith PF, Maclennan K, Darlington CL. The meuroprotective peroperties of the Ginkgo biloba leaf: A review of the possible relationship to platelet-activating factor PAF. J Ethnopharmacol

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract