培哚普利和依那普利对ApoE基因敲除小鼠动脉粥样硬化进展影响的实验研究
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摘要
目的:
探讨血管紧张素转换酶抑制剂(ACEI)对ApoE基因敲除小鼠动脉粥样硬化病变进展的影响,特别是对斑块成分的影响,并比较培哚普利与依那普利疗效的差别。
方法:
ApoE基因敲除小鼠随机分为培哚普利组、依那普利组及对照组3组。对主动脉根部斑块进行定量分析,并评估斑块胶原含量及脂核面积。以冰冻切片进行免疫荧光检查,观察斑块内单核细胞/巨噬细胞-2(MOMA-2)、细胞间粘附分子-1(ICAM-1)、血管细胞粘附分子-1(VCAM-1)、基质金属蛋白酶-9(MMP-9)的表达。
结果:
各实验组之间的血压、血脂无显著性差别。与对照组比较,培哚普利组与依那普利组的斑块面积分别减少了25.33%和22.86%(P均＜0.01),但是两组ACEI的斑块面积差异无统计学意义。培哚普利组与依那普利组减小脂核面积(分别为52.98%及38.98%,P均＜0.01)及MOMA-2(分别为88.38%及52.16%,P均＜0.01)、ICAM-1(分别为80.87%及49.59%,P均＜0.01)、VCAM-1(分别为77.56%及56.44%,P均＜0.01)、MMP-9(分别为86.93%及55.56%,P均＜0.01)的表达,并增加斑块胶原含量(分别为298.36%及168.14%,P均＜0.01),而且培哚普利组在这些方面均显著优于依那普利组(P均＜0.05)。
结论:
ACEI在不影响血脂和血压的情况下可以抑制ApoE基因敲除小鼠动脉粥样硬化斑块的炎症并延缓动脉粥样硬化的进展。尽管培哚普利和依那普利在减少斑块面积方面差异无统计学意义,但是培哚普利在稳定斑块方面优于依那普利。
目的:
探讨培哚普利对ApoE基因敲除小鼠冠状动脉和主动脉根部动脉粥样硬化进展的影响。
方法:
20只ApoE基因敲除小鼠随机分为培哚普利组(1-5mg.kg~(-1).d~(-1),n=10)及对照组(生理盐水,0.2ml/d,n=10),20周后处死小鼠。切片以改良Movat五色套染法染色后,对冠状动脉和主动脉根部斑块面积进行定量分析。
结果:
与对照组比较,培哚普利组的冠状动脉斑块面积(分别为81599±6041μm~2及65718±5059μm~2,P＜0.01)和主动脉根部斑块面积(分别为937678±90445μm~2及700148±72537μm~2,P＜0.01)明显减少。对照组的冠状动脉斑块面积与主动脉根部斑块面积呈正相关(r=0.791,P＜0.01),培哚普利组的冠状动脉斑块面积与主动脉根部斑块面积也呈正相关(r=0.721,P＜0.05)。
结论:
培哚普利既减少冠状动脉斑块的面积,也减少主动脉根部斑块的面积。冠状动脉斑块面积与主动脉根部斑块面积密切相关。
Objective
To investigate the effects of angiotensin converting enzyme(ACE) inhibitors on the development of atherosclerotic lesions,particularly on the composition of plaque,in ApoE knockout mice,and to compare the different effects between perindopril and enalapril.
Methods
ApoE knockout mice were treated with perindopril(1.5mg·kg~(-1)·d~(-1), n=20),or enalapril(7.5 mg·kg~(-1)·d~(-1),n=20)or saline(0.2 ml/d,n=20) per gavage for 20 weeks.Blood pressure and lipids were measured at the study end.Aortic root atherosclerotic plaque was then quantified and the content of collagen and the size of lipid core in the plaque were assessed. Cryostat sections were used to quantify the expressions of monocyte/macrophage-2(MOMA-2),intercellular adhesion molecule-1 (ICAM-1),vascular cell adhesion molecule-1(VCAM-1) and matrix metalloproteinases-9(MMP-9) in the plaque by immunofluorescence method.
Results
Blood pressure and lipid profiles were similar among different groups.Compared with control group,the plaque areas of perindopril group and enalapril group displayed significant decrease(25.33%and 22.86%,respectively,both P＜0.01).However,no significant differences were observed in the plaque size between the different ACE inhibitor groups.It was demonstrated that in perindopril group and enalapril group the size of lipid core significantly decreased(52.98%and 38.98%, respectively,both P＜0.01) and the expression of MOMA-2(88.38%and 52.16%,respectively,both P＜0.01),ICAM-1(80.87%and 49.59%, respectively,both P＜0.01),VCAM-1(77.56%and 56.44%,respectively, both P＜0.01) and MMP-9(86.93%and 55.56%,respectively,both P＜0.01) also significantly decreased,and the plaque collagen content increased significantly(298.36%and 168.14%,respectively,both P＜0.01) and the effects of perindopril were superior to those of enalapril(all P＜0.05).
Conclusions
ACE inhibitors significantly suppressed tissue inflammation and attenuated the development of atherosclerosis in ApoE knockout mice independent of their effects on the lipid and blood pressure.Perindopril is superior to enalapril in stabilizing the plaques and has similar effect on reducing the plaque size as that of enalapril.
Objective
To investigate the effects of perindopril on the development of atherosclerotic lesions in coronary artery and aortic root of ApoE knockout mice.
Methods
Twenty ApoE knockout mice were randomly divided into two groups:perindoprilor group(1.5mg·kg~(-1)·d~(-1),n=10) and control group (saline,0.2 ml/d,n=10).These mice were sacrificed after 20 weeks.The plaque areas of coronary artery and aortic root were measured after the sections were stained with a modified Movat pentachrome stain.
Results
Compared with control group,plaque areas of coronary artery (81599±6041μm~2 and 65718±5059μm~2,respectively,P＜0.01) and aortic root(937678±90445μm~2 and 700148±72537μm~2,respectively, P＜0.01) in perindopril group were significantly decreased.The plaque areas of coronary artery were positively correlated with the plaque areas of aortic root in perindopril group(r=0.791,P＜0.01).The plaque areas of coronary artery were also positively correlated with the plaque areas of aortic root in control group(r=0.721,P＜0.05).
Conclusions
Perindopril not only decreases plaque areas of coronary artery but also decreases plaque areas of aortic root.The plaque areas of coronary artery are closely correlated with the plaque areas of aortic root.
探讨血管紧张素转换酶抑制剂(ACEI)对ApoE基因敲除小鼠动脉粥样硬化病变进展的影响,特别是对斑块成分的影响,并比较培哚普利与依那普利疗效的差别。
方法:
ApoE基因敲除小鼠随机分为培哚普利组、依那普利组及对照组3组。对主动脉根部斑块进行定量分析,并评估斑块胶原含量及脂核面积。以冰冻切片进行免疫荧光检查,观察斑块内单核细胞/巨噬细胞-2(MOMA-2)、细胞间粘附分子-1(ICAM-1)、血管细胞粘附分子-1(VCAM-1)、基质金属蛋白酶-9(MMP-9)的表达。
结果:
各实验组之间的血压、血脂无显著性差别。与对照组比较,培哚普利组与依那普利组的斑块面积分别减少了25.33%和22.86%(P均＜0.01),但是两组ACEI的斑块面积差异无统计学意义。培哚普利组与依那普利组减小脂核面积(分别为52.98%及38.98%,P均＜0.01)及MOMA-2(分别为88.38%及52.16%,P均＜0.01)、ICAM-1(分别为80.87%及49.59%,P均＜0.01)、VCAM-1(分别为77.56%及56.44%,P均＜0.01)、MMP-9(分别为86.93%及55.56%,P均＜0.01)的表达,并增加斑块胶原含量(分别为298.36%及168.14%,P均＜0.01),而且培哚普利组在这些方面均显著优于依那普利组(P均＜0.05)。
结论:
ACEI在不影响血脂和血压的情况下可以抑制ApoE基因敲除小鼠动脉粥样硬化斑块的炎症并延缓动脉粥样硬化的进展。尽管培哚普利和依那普利在减少斑块面积方面差异无统计学意义,但是培哚普利在稳定斑块方面优于依那普利。
目的:
探讨培哚普利对ApoE基因敲除小鼠冠状动脉和主动脉根部动脉粥样硬化进展的影响。
方法:
20只ApoE基因敲除小鼠随机分为培哚普利组(1-5mg.kg~(-1).d~(-1),n=10)及对照组(生理盐水,0.2ml/d,n=10),20周后处死小鼠。切片以改良Movat五色套染法染色后,对冠状动脉和主动脉根部斑块面积进行定量分析。
结果:
与对照组比较,培哚普利组的冠状动脉斑块面积(分别为81599±6041μm~2及65718±5059μm~2,P＜0.01)和主动脉根部斑块面积(分别为937678±90445μm~2及700148±72537μm~2,P＜0.01)明显减少。对照组的冠状动脉斑块面积与主动脉根部斑块面积呈正相关(r=0.791,P＜0.01),培哚普利组的冠状动脉斑块面积与主动脉根部斑块面积也呈正相关(r=0.721,P＜0.05)。
结论:
培哚普利既减少冠状动脉斑块的面积,也减少主动脉根部斑块的面积。冠状动脉斑块面积与主动脉根部斑块面积密切相关。
Objective
To investigate the effects of angiotensin converting enzyme(ACE) inhibitors on the development of atherosclerotic lesions,particularly on the composition of plaque,in ApoE knockout mice,and to compare the different effects between perindopril and enalapril.
Methods
ApoE knockout mice were treated with perindopril(1.5mg·kg~(-1)·d~(-1), n=20),or enalapril(7.5 mg·kg~(-1)·d~(-1),n=20)or saline(0.2 ml/d,n=20) per gavage for 20 weeks.Blood pressure and lipids were measured at the study end.Aortic root atherosclerotic plaque was then quantified and the content of collagen and the size of lipid core in the plaque were assessed. Cryostat sections were used to quantify the expressions of monocyte/macrophage-2(MOMA-2),intercellular adhesion molecule-1 (ICAM-1),vascular cell adhesion molecule-1(VCAM-1) and matrix metalloproteinases-9(MMP-9) in the plaque by immunofluorescence method.
Results
Blood pressure and lipid profiles were similar among different groups.Compared with control group,the plaque areas of perindopril group and enalapril group displayed significant decrease(25.33%and 22.86%,respectively,both P＜0.01).However,no significant differences were observed in the plaque size between the different ACE inhibitor groups.It was demonstrated that in perindopril group and enalapril group the size of lipid core significantly decreased(52.98%and 38.98%, respectively,both P＜0.01) and the expression of MOMA-2(88.38%and 52.16%,respectively,both P＜0.01),ICAM-1(80.87%and 49.59%, respectively,both P＜0.01),VCAM-1(77.56%and 56.44%,respectively, both P＜0.01) and MMP-9(86.93%and 55.56%,respectively,both P＜0.01) also significantly decreased,and the plaque collagen content increased significantly(298.36%and 168.14%,respectively,both P＜0.01) and the effects of perindopril were superior to those of enalapril(all P＜0.05).
Conclusions
ACE inhibitors significantly suppressed tissue inflammation and attenuated the development of atherosclerosis in ApoE knockout mice independent of their effects on the lipid and blood pressure.Perindopril is superior to enalapril in stabilizing the plaques and has similar effect on reducing the plaque size as that of enalapril.
Objective
To investigate the effects of perindopril on the development of atherosclerotic lesions in coronary artery and aortic root of ApoE knockout mice.
Methods
Twenty ApoE knockout mice were randomly divided into two groups:perindoprilor group(1.5mg·kg~(-1)·d~(-1),n=10) and control group (saline,0.2 ml/d,n=10).These mice were sacrificed after 20 weeks.The plaque areas of coronary artery and aortic root were measured after the sections were stained with a modified Movat pentachrome stain.
Results
Compared with control group,plaque areas of coronary artery (81599±6041μm~2 and 65718±5059μm~2,respectively,P＜0.01) and aortic root(937678±90445μm~2 and 700148±72537μm~2,respectively, P＜0.01) in perindopril group were significantly decreased.The plaque areas of coronary artery were positively correlated with the plaque areas of aortic root in perindopril group(r=0.791,P＜0.01).The plaque areas of coronary artery were also positively correlated with the plaque areas of aortic root in control group(r=0.721,P＜0.05).
Conclusions
Perindopril not only decreases plaque areas of coronary artery but also decreases plaque areas of aortic root.The plaque areas of coronary artery are closely correlated with the plaque areas of aortic root.
引文
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18. Heo HJ, Yun MR, Jung KH, et al. Endogenous angiotensin II enhances atherogenesis in apoprotein E-deficient mice with renovascular hypertension through activation of vascular smooth muscle cells. Life Sci,2007,80:1057-1063.
19. Sawamura T ,Kume N ,Aoyama T ,et al .An endothelial receptor for oxidized low-density Lipoprotein.Nature,1997,386:73-77.
20.Li DY,Zhang YC,Philips MI,et al .Upregulation of endothelial receptor for oxidized low-density lipoprotein (Lox-1) in cultured human coronary artery endothelial cells by angiotensin II type I receptor activation.Cir Res,1999,84:1043-1049.
21.Keidar S, Attias J, Heinrich,et al. Angiotensin II atherogenicity in apolipoprotein E deficient mice is associated with increased cellular cholesterol biosynthesis. Atherosclerosis,1999,146:249-257.
22. Won SM, Park YH, Kim HJ,et al. Catechins inhibit angiotensin II-induced vascular smooth muscle cell proliferation via mitogen-activated protein kinase pathway. Exp Mol Med,2006 ,38:525-534.
23.Tamarat R, Silvestre JS, Durie M, et al.Angiotensin II angiogenic efect in vivo involves vascular endothelial growth factor- and inflammation-related pathways.Lab Invest.2002,82:747-756.
24. Hilfiker A, Hilfiker-Kleiner D, Fuchs M. Expression of CYR61, an angiogenic immediate earlyg ene,in arteriosclerosis and its regulation by angiotensin II. Circulation,2002,106:254-260.
25.Nishimura H,Tsuji H,Masuda Het al.The effect of angiotensin metabolites on the regulation of coagulation and fibrinolysis in culured rat aortic endothelial cells.Thromb Haemost,1999,82:1516-1521.
26.Batenburg WW,Popp R,Fleming I,et al.Bradykinin-induced relaxation of coronary microarteries S-nitrosothiols as EDHF.Br J Pharmacol,2004,142:125-135.
1. Prescott MF,Hasler-Rapacz J,von Linden-Reed J,et al.Familial hypercholesterolemia associated with coronary atherosclerosis in swine bearing different alleles for apolipoprotein B.Ann NY Acad Sci,1995,748:283-292.
2. Jerome WG,Lewis JC. Cellular dynamics in early atherosclerotic lesion progression in white carneau pigeon-spatial and temporal analysis of monocyte and smooth muscle invasion of the intima.Arterioscler Thromb Vasc Biol.1997,15-.654-664.
3. Yancey PG,St.Clair RW.Mechanism of the defect in cholesteryl ester clearance from macrophages of atherosclerosis-susceptible white carneau pigeon.J Lipid Res.l994,35:2114-2129.
4. Paigen B, Morrow C, Brandon C et al. Variation in susceptibility to atherosclerosis among inbtred strains of mice. Atherosclerosis 1985;57: 65-73.
5. Jean L,Stewart P,John L.Pathology of atherosclerosis in cholesterol—fed,susceptible mice,Atherosclerosis,1991,90:211—218.
6. Roberts A,Thompson JS. Genetic factors in the development of atheroma and on serum total cholesterol levels in inbred mice and their hybrids. Prog Biochem Pharmacol,1977,13:298—305.
7. Piedrahita JA, Zhang SH, Hagaman JR,et al. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. PNAS,1992, 89:4471-4475.
8. Plump AS, Smith JD, Hayek T, Aalto-Setela K et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E -deficient mice created by homologous recombination in ES cells.Cell, 1992, 71:343-353.
9. Nakashima Y,Plump AS,Raines EW,et al.ApoE-deficient mice develop lesions of all phases of atherosclerosis thoughout the arterial tree.ArteriosclerThromb,1994,14:133-140.
10. Reddick RL,Zhang SH,Maeda N. Arteriosclerosis in mice lacking ApoE -evaluation of lesional development and progression.Arteriosclerosis and Thrombosis,1994,14:141-147.
11. Ishibashi S, Brown MS, Goldstein JL, et al. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus - mediated gene delivery. J Clin Invest,1993,92: 883-893.
12. Ishibashi S, Herz J, Maeda N, et al. The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc Natl Acad Sci USA,1994,91:4431-4435.
13. Witting PK, Pettersson K, Ostlund-Lindqvist AM, et al.Inhibition by a coantioxidant of aortic lipoprotein lipid peroxydation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice. FASEB J,1999,13: 667-675.
14. Linton MF, Farese RJ, Chiesa G et al. Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein (a). J Clin Invest, 1993, 92:3029-3037.
15. Wissler RW,Eilert ML,Schroeder MA,et al. Production of lipormatous and atheromatous arterial lesions in the albino rat. AMA Arch Pathol,1954,57:333-351.
16. Bujan J,Bellon JM,Sabater C.et al.Modifications induced by atherogenic diet in the capacity of the arterial wall in rats to respond to surgical insult. Atherosclerosis, 1996,122:141-152.
17. Joen RS,Ching HW,Yi CC,et al. Mechanisms in the inhibition of neointimal hyperplasis with triflavin in a rat model of balloon angioplasty. J Lab Clin Med,2001,13:270-277.
18. Fishman JA,Graeme BR,Morris JK,et al. Endothelial regrneration in the rat carotid artery and the significance of endothelial denudation in the pathogenesis of myointimal thickening. Lab Invest, 1975,32:339-351.
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20. Ari M,Sinikka T,Jorma H. Chronic rejection in rat aortic allografts.Arterioscler Thromb,1991,11:671-680.
21. Loree HM,Kamm RD,Stringfellow RG, et al. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res, 1992,71:850-858.
22. Bea F,Blessing E,Bennett B.Simvastatin promotes atherosclerotic plaques stability in apoE-deficient mice independently of lipid lowering.Arterioscler Thromb Vasc Biol,2002,22:1832-1837.
23. Ge J,Chirillo F,Schwedtmann J,et al.Screening of ruptured plaques in patients with coronary artery disease by intravascular ultrasound.Heart,1999,81:621-627.
24. Yamagishi M,Umeno T,Hongo Y,et al.Intravascular ultrasonic evidence for importance of plaque distribution(eccentric vs circumferential) indetermining distensibility of the left anterior descending artery . Am J Cardiol, 1997,79:1596-1600.
25.Tenaglia AN,Peters KG,Sketch MH,et al.Neovascularization in atherectomy specimens from patients with unstable angina: implications for pathogenesis of unstable angina.Am Heart J,1998,135:10-14.
26. Gerckens U,Buellesfeld L,McNamara E,et al.Optical Coherence Tomography(OCT).Potential of a new high-resolution intracoronary imaging technique.Herz Sep,2003,28:496-500.
27. Schoenhagen P,Ziada KM,Kapadia SR,et al.Extent and direction of arterial remodeling in stable and unstable coronary syndromes.Circulation,2000,101:598-603.
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1. Bea F,Kreuzer J,Preusch M,et al. Melagatran reduces advanced atherosclerotic lesion size and may promote plaque stability in apolipoprotein E-deficient mice., 2006,26:2787-2792.
2. Johnson JL, Fritsche-Danielson R, Behrendt M,et al. Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stability. Cardiovasc Res,2006,71:586-595.
3. Johnson JL, Baker AH, Oka K,et al. Suppression of atherosclerotic plaque progression and instability by tissue inhibitor of metalloproteinase-2: involvement of macrophage migration and apoptosis.Circulation,2006,113:2435-2444.
4. Rosenfeld ME,Polinsky P,Virmani R,et al.Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse.Arterioscler Thromb Vasc Biol, 2000, 20:2587-2592.
5. Maguire JJ, Wiley KE, Kuc RE, Endothelin-mediated vasoconstriction in early atherosclerosis is markedly increased in ApoE-/- mouse but prevented by atorvastatin. Exp Biol Med .2006,231:806-812
6. Takaya T,Kawashima S,Shinohara M,et al.Angiotensin II type 1 receptor blocker telmisartan suppresses superoxide production and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. Atherosclerosis, 2006,186:402-410.
7. Landmesser U, Spiekermann S, Preuss C,et al. Angiotensin II induces endothelial xanthine oxidase activation: role for endothelial dysfunction in patients with coronary disease. Arterioscler Thromb Vasc Biol,2007,27:703-704.
8. Tham DM,Martin-McNulty B ,Wang YX,et a l.Angiotensin II is associated with activation of N F-kB -mediated genes and downregulation of PPARs.Physiol Genomics,2002,11: 21-30.
9. Funakoshi Y,Ichiki T, Shimokawa H, et al. Rho-kinase mediates angiotensin II -induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells. Hypertension,2001,38 :100-104.
10. Nakashima Y,Plump AS,Raines EW,et al.ApoE-deficient mice develop lesions of all phases of atherosclerosis thoughout the arterial tree.ArteriosclerThromb,1994,14:133-140.
11. Reddick RL,Zhang SH,Maeda N. Arteriosclerosis in mice lacking ApoE -evaluation of lesional development and progression. Arteriosclerosis and Thrombosis,1994,14:141-147.
12. Hu W,Polinsky P,Sadoun E,et al.Atherosclerotic lesions in the common coronary arteries of ApoE knockout mice.Cardiovasc Pathol,2005,14:120-125
13. Rodriguez-Granillo GA,Vos J,Bruining N,et al. Long-term effect of perindopril on coronary atherosclerosis progression (from the perindopril's prospective effect on coronary atherosclerosis by angiography and intravascular ultrasound evaluation [PERSPECTIVE] study).Am J Cardiol,2007,100:159-163.
14. Rajagopalan S,Kurz S,Mmzel T ,et al.Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADP/NADPH oxidase activation.J Clin Invest, 1996,97:1916-1923.
15. Rueckschloss U, Quinn MT, Holtz J, Morawietz H. Dose-dependent regulation of N -AD(P)H oxidase expression by angiotensin 11 in human endothelial cells: protective effect of angiotensin lltype 1 receptor blockade in patients with cor onary artery disease.Arterioscler Thromb Vase Biol,2002,22:1845-1851.
16. Landmesser U, Spiekermann S, Preuss C,et al. Angiotensin II induces endothelial xanthine oxidase activation: role for endothelial dysfunction in patients with coronary disease. Arterioscler Thromb Vasc Biol,2007,27:703-704.
17. Keidar S ,Heinrich R ,Kaplan M ,et al.Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized LDL:a possible role for interleukin-6.Arterioscler Thromb Vase Biol,2001,21:1464-1469.
18. Heo HJ, Yun MR, Jung KH, et al. Endogenous angiotensin II enhances atherogenesis in apoprotein E-deficient mice with renovascular hypertension through activation of vascular smooth muscle cells. Life Sci,2007,80:1057-1063.
19. Sawamura T ,Kume N ,Aoyama T ,et al .An endothelial receptor for oxidized low-density Lipoprotein.Nature,1997,386:73-77.
20.Li DY,Zhang YC,Philips MI,et al .Upregulation of endothelial receptor for oxidized low-density lipoprotein (Lox-1) in cultured human coronary artery endothelial cells by angiotensin II type I receptor activation.Cir Res,1999,84:1043-1049.
21.Keidar S, Attias J, Heinrich,et al. Angiotensin II atherogenicity in apolipoprotein E deficient mice is associated with increased cellular cholesterol biosynthesis. Atherosclerosis,1999,146:249-257.
22. Won SM, Park YH, Kim HJ,et al. Catechins inhibit angiotensin II-induced vascular smooth muscle cell proliferation via mitogen-activated protein kinase pathway. Exp Mol Med,2006 ,38:525-534.
23.Tamarat R, Silvestre JS, Durie M, et al.Angiotensin II angiogenic efect in vivo involves vascular endothelial growth factor- and inflammation-related pathways.Lab Invest.2002,82:747-756.
24. Hilfiker A, Hilfiker-Kleiner D, Fuchs M. Expression of CYR61, an angiogenic immediate earlyg ene,in arteriosclerosis and its regulation by angiotensin II. Circulation,2002,106:254-260.
25.Nishimura H,Tsuji H,Masuda Het al.The effect of angiotensin metabolites on the regulation of coagulation and fibrinolysis in culured rat aortic endothelial cells.Thromb Haemost,1999,82:1516-1521.
26.Batenburg WW,Popp R,Fleming I,et al.Bradykinin-induced relaxation of coronary microarteries S-nitrosothiols as EDHF.Br J Pharmacol,2004,142:125-135.
1. Prescott MF,Hasler-Rapacz J,von Linden-Reed J,et al.Familial hypercholesterolemia associated with coronary atherosclerosis in swine bearing different alleles for apolipoprotein B.Ann NY Acad Sci,1995,748:283-292.
2. Jerome WG,Lewis JC. Cellular dynamics in early atherosclerotic lesion progression in white carneau pigeon-spatial and temporal analysis of monocyte and smooth muscle invasion of the intima.Arterioscler Thromb Vasc Biol.1997,15-.654-664.
3. Yancey PG,St.Clair RW.Mechanism of the defect in cholesteryl ester clearance from macrophages of atherosclerosis-susceptible white carneau pigeon.J Lipid Res.l994,35:2114-2129.
4. Paigen B, Morrow C, Brandon C et al. Variation in susceptibility to atherosclerosis among inbtred strains of mice. Atherosclerosis 1985;57: 65-73.
5. Jean L,Stewart P,John L.Pathology of atherosclerosis in cholesterol—fed,susceptible mice,Atherosclerosis,1991,90:211—218.
6. Roberts A,Thompson JS. Genetic factors in the development of atheroma and on serum total cholesterol levels in inbred mice and their hybrids. Prog Biochem Pharmacol,1977,13:298—305.
7. Piedrahita JA, Zhang SH, Hagaman JR,et al. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. PNAS,1992, 89:4471-4475.
8. Plump AS, Smith JD, Hayek T, Aalto-Setela K et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E -deficient mice created by homologous recombination in ES cells.Cell, 1992, 71:343-353.
9. Nakashima Y,Plump AS,Raines EW,et al.ApoE-deficient mice develop lesions of all phases of atherosclerosis thoughout the arterial tree.ArteriosclerThromb,1994,14:133-140.
10. Reddick RL,Zhang SH,Maeda N. Arteriosclerosis in mice lacking ApoE -evaluation of lesional development and progression.Arteriosclerosis and Thrombosis,1994,14:141-147.
11. Ishibashi S, Brown MS, Goldstein JL, et al. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus - mediated gene delivery. J Clin Invest,1993,92: 883-893.
12. Ishibashi S, Herz J, Maeda N, et al. The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc Natl Acad Sci USA,1994,91:4431-4435.
13. Witting PK, Pettersson K, Ostlund-Lindqvist AM, et al.Inhibition by a coantioxidant of aortic lipoprotein lipid peroxydation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice. FASEB J,1999,13: 667-675.
14. Linton MF, Farese RJ, Chiesa G et al. Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein (a). J Clin Invest, 1993, 92:3029-3037.
15. Wissler RW,Eilert ML,Schroeder MA,et al. Production of lipormatous and atheromatous arterial lesions in the albino rat. AMA Arch Pathol,1954,57:333-351.
16. Bujan J,Bellon JM,Sabater C.et al.Modifications induced by atherogenic diet in the capacity of the arterial wall in rats to respond to surgical insult. Atherosclerosis, 1996,122:141-152.
17. Joen RS,Ching HW,Yi CC,et al. Mechanisms in the inhibition of neointimal hyperplasis with triflavin in a rat model of balloon angioplasty. J Lab Clin Med,2001,13:270-277.
18. Fishman JA,Graeme BR,Morris JK,et al. Endothelial regrneration in the rat carotid artery and the significance of endothelial denudation in the pathogenesis of myointimal thickening. Lab Invest, 1975,32:339-351.
19. Castellanos E,Sueishi K,Tanaka K,et al. Ultrastructural studies of rat arteriosclerosis induced by stimulation of the immune system with ovalbumin. Acta Pathol JPN,1991,41:113-121.
20. Ari M,Sinikka T,Jorma H. Chronic rejection in rat aortic allografts.Arterioscler Thromb,1991,11:671-680.
21. Loree HM,Kamm RD,Stringfellow RG, et al. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res, 1992,71:850-858.
22. Bea F,Blessing E,Bennett B.Simvastatin promotes atherosclerotic plaques stability in apoE-deficient mice independently of lipid lowering.Arterioscler Thromb Vasc Biol,2002,22:1832-1837.
23. Ge J,Chirillo F,Schwedtmann J,et al.Screening of ruptured plaques in patients with coronary artery disease by intravascular ultrasound.Heart,1999,81:621-627.
24. Yamagishi M,Umeno T,Hongo Y,et al.Intravascular ultrasonic evidence for importance of plaque distribution(eccentric vs circumferential) indetermining distensibility of the left anterior descending artery . Am J Cardiol, 1997,79:1596-1600.
25.Tenaglia AN,Peters KG,Sketch MH,et al.Neovascularization in atherectomy specimens from patients with unstable angina: implications for pathogenesis of unstable angina.Am Heart J,1998,135:10-14.
26. Gerckens U,Buellesfeld L,McNamara E,et al.Optical Coherence Tomography(OCT).Potential of a new high-resolution intracoronary imaging technique.Herz Sep,2003,28:496-500.
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