1997 년도산학협동연구비수혜논문 Korean Circulation J 2000;304:517-527 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;304:517-527 KEY WORDSApolipoprotein E deficient mouse Atherosclerosis Vascular remodel Primary prevention. 서 론 517
518 연구방법 Korean Circulation J 2000;304:517-527
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/B16 117.2 26.4 92.0 57.4 Control apoe / 550.3204.0 173.7149.4 ApoE /asprin 903.7104.7 186.0104.0 ApoE/methotrexate 826.3274.0 201.8111.3 ApoE/probucol 827.5355.6 113.0 51.6 ApoE/sulodexide 940.7201.2 286.0155.0 ApoE/diltiazem 998.3286.2 227.8110.8 ApoE/cilazapril 964.7249.6 189.2 66.8 ApoE/molsidomine 1022.7125.2 293.7145.3 ApoE/trimetazidine 907.4122.4 156.2 58.4 ApoE/pentoxiphyline 911.2216.0 207.3100.6 519
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 1 3 3 2 2 3 3 3 19 2 2 1 2 2 1 0 0.5 8.5 3 3 2 2 2 3 3 3 18 4 3 2.5 2 3 1 3 2.5 17 5 3 2 2 3 0 2.5 2.5 15 6 3 2.5 2 3 2.5 2.5 2 17.5 ApoE /asprin 1 2.5 2.5 2 3 2 1 0 13 2 0.5 0.5 2 0 0 0 0 3 3 2.5 2.5 2 2 0 0 0 9 ApoE /methotrexate 1 0 1.5 2 2 0 0 0 5.5 2 0 1.5 2 2.5 2 1 1 10 3 1.5 2 2 2 2 3 3 14.5 4 0 0 2 3 2 0 0 7 5 0 2 2 2 0 0 0 6 6 0 0 2 3 1 1.5 0 7.5 ApoE /probucol 1 2.5 0 2 3 0 1 1.5 10 2 1 1 2 2 0 1 0 7 3 0.5 0 2 2 0 0 0 4.5 4 0 0 2 2 0 0 0 4 ApoE /sulodexide 1 0 0 2 0 0 0 0 2 2 2 2 2 2 0 1 0 9 3 1.5 2 2 0 0 0 0 5.5 4 1 2 2 3 0 0 0 8 5 1 1 2 3 0 0 0 7 6 3 2.5 2 3 0 0 0 10.5 ApoE /diltiazem 1 0 0 2 2 2 2 0 8 2 0 1 2 2 2 0 0 7 3 0 2 2 2 0 1 0 7 4 2.5 0 2 2 0 1 0 7.5 5 2.5 0 2 2 2 0 0 8.5 6 2 1 2 3 0 0 0 8 ApoE /cilazapril 1 2.5 0 2 2 1 1 0 8.5 2 0.5 0 2 1 0 2 0 5.5 3 1 0 2 2 3 0 0 8 4 1 0 2 3 0 0 0 8 5 0 2 2 2 0 0 0 6 6 1.5 0 2 1 1 1 0 6.5 520 Korean Circulation J 2000;304:517-527
Table 2. Continued ApoE ECA score CCA score AA score AR score IT score FA score PA score Sum of score ApoE /molsidomine 1 1 2 2 1 2 3 0 11 2 1.5 0 2 3 0 1 0 7.5 3 3 0 2 3 0 1 0 9 4 3 0 2 3 0 0 0 8 5 0.5 0.5 2 0 0 0 0 3 6 0 3 2 2 3 3 0 14 ApoE /trimetazidine 1 3 2.5 2 2 3 2.5 0 15 2 2.5 0 2 3 2 1 0 10.5 3 3 1 2 2 3 1 0 12 4 0 0 2 0 0 0 0 2 5 0 0 2 2 0 0 0 4 ApoE /pentoxiphyline 1 0 0 2 2 0 0 0 4 2 0 0 2 1 0 0 0 3 3 2 0 2 1.5 0 0.5 0 6 4 2.5 1.5 2 1 0 0 0 7 5 1 0 2 1 0 0 0 4 6 1 2.5 2 1 1 1.5 0 9 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 69/7295.8 Aspirin 2/ 5 0/ 2 3/3 1/2 0/ 6 0/ 6 1/ 6 7/3023.3 Methotrexate 0/ 9 4/10 6/6 3/6 1/11 0/11 0/ 7 14/6023.3 Probucol 1/ 7 1/ 8 5/5 4/5 0/ 8 0/ 8 0/ 6 11/4723.4 Sulodexide 0/12 2/12 6/6 4/6 0/ 8 0/10 0/ 4 12/5820.7 Dilitiazem1 1/12 1/12 5/6 1/6 1/11 0/11 0/10 9/6813.2 Cilazapril 0/12 0/ 9 6/6 4/6 1/11 0/10 0/ 7 11/6118.0 Molsidomine 6/11 1/10 6/6 4/6 1/11 0/12 0/11 18/6728.9 Trimetazidine 3/ 7 2/10 5/5 2/5 1/10 0/12 0/11 12/6020.0 Pentoxiphyline 0/12 1/ 6 5/6 2/5 2/10 0/12 0/ 8 10/5916.9 GNX 1/ 8 3/ 8 5/5 3/5 0/10 1/ 8 1/ 8 14/5226.9 EC=external carotid arterycc=common carotid arteryaa=aortic achar=aorta at the level of kidney IT=iliac trifurcation arteryfa=femoral arterypa=popliteal artery 521
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 69/7295.8 Aspirin 1/ 5 1/ 2 1/3 0/2 0/ 6 0/ 6 0/ 6 3/33 9.1 Methotrexate 0/ 9 2/10 6/6 1/6 0/11 0/11 0/ 7 9/6015.0 Probucol 0/ 7 1/ 8 2/5 1/5 0/ 8 0/ 8 0/ 6 4/47 8.5 Sulodexide 0/12 2/12 6/6 1/6 0/ 8 0/10 0/ 4 7/5812.1 Dilitiazem1 1/12 1/12 3/6 0/6 1/11 0/11 0/10 6/68 8.8 Cilazapril 0/12 0/ 9 2/6 2/6 0/11 0/10 0/ 7 4/61 6.6 Molsidomine 1/11 0/10 3/6 2/6 0/11 0/12 0/11 6/67 9.0 Trimetazidine 0/ 7 1/10 2/5 1/5 0/10 0/12 0/11 4/60 6.7 Pentoxiphyline 0/12 0/ 6 3/6 0/5 0/10 0/12 0/ 8 3/59 5.1 GNX 1/ 8 2/ 8 4/5 3/5 0/10 0/ 8 0/ 8 10/5219.2 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 69/7295.8 Aspirin 2/ 5 0/ 2 2/3 0/2 0/ 6 0/ 6 0/ 6 4/3315.2 Methotrexate 0/ 9 1/10 5/6 4/6 2/11 0/11 0/ 7 12/6020.0 Probucol 1/ 7 2/ 8 3/5 1/5 0/ 8 1/ 8 0/ 6 8/4717.2 Sulodexide 1/12 2/12 4/6 4/6 0/ 8 0/10 0/ 4 11/5817.2 Dilitiazem1 1/12 0/12 1/6 1/6 1/11 0/11 0/10 4/68 5.9 Cilazapril 0/12 0/ 9 6/6 0/6 0/11 0/10 0/ 7 6/6111.5 Molsidomine 3/11 0/10 3/6 2/6 2/11 2/12 0/11 12/6717.9 Trimetazidine 1/ 7 2/10 4/5 2/5 1/10 1/12 0/11 11/6018.3 Pentoxiphyline 0/12 0/ 6 1/6 1/5 0/10 0/12 0/ 8 2/5910.2 GNX 1/ 8 1/ 8 0/5 1/5 0/10 1/ 8 0/ 8 5/5221.2 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 69/7295.8 Aspirin 1/ 5 1/ 2 1/3 2/2 0/ 6 0/ 6 0/ 6 5/3315.2 Methotrexate 0/ 9 1/10 5/6 4/6 2/11 0/11 0/ 7 12/6020.0 Probucol 1/ 7 2/ 8 3/5 1/5 0/ 8 1/ 8 0/ 6 8/4717.2 Sulodexide 1/12 1/12 4/6 3/6 0/ 8 1/10 0/ 4 10/5817.2 Dilitiazem1 1/12 0/12 1/6 1/6 1/11 0/11 0/10 4/68 5.9 Cilazapril 0/12 0/ 9 4/6 1/6 1/11 1/10 0/ 7 7/6111.5 Molsidomine 3/11 0/10 3/6 2/6 2/11 2/12 0/11 12/6717.9 Trimetazidine 1/ 7 2/10 4/5 2/5 1/10 1/12 0/11 11/6018.3 Pentoxiphyline 0/12 0/ 6 3/6 2/5 1/10 0/12 0/ 8 6/5910.2 GNX 0/ 8 1/ 8 5/5 3/5 0/10 1/ 8 1/ 8 11/5221.2 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;304:517-527
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
524 Korean Circulation J 2000;304:517-527
본연구의한계점 : 연구배경 : 요약 방법 : 결과 : 525
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