臺灣博碩士論文加值系統

腦及心臟血管疾病主要肇因於動脈血管平滑肌的病變。牡丹皮是傳統中藥具活血化瘀作用，丹皮酚為牡丹皮的主要成分之一，根據現代文獻報告，具有許多生物活性，如抗炎、抗過敏、抗腫瘤、抗血管新生和抗氧化等作用。本研究試就牡丹皮萃取物對於小鼠頸動脈損傷後內膜增生的影響，以及探討牡丹皮萃取物和牡丹酚對於血管平滑肌細胞的增生和遷移之作用機轉。
實驗結果顯示，牡丹皮萃取物有效減少ICR小鼠左側頸動脈結紮所導致的血管內膜增生，在H&E實驗其抑制率為24 % (0.1 g/Kg)與37 % (0.2 g/Kg)；對PCNA stain實驗其抑制率為35 % (0.1 g/Kg)與62 % (0.2 g/Kg)。在細胞學實驗：Wound healing和Transwell的實驗結果顯示，牡丹皮萃取物和牡丹酚可有效抑制PDGF誘導的血管平滑肌細胞增生和遷移。由西方墨點法 (Western blotting)分析，結果顯示，牡丹皮萃取物及牡丹酚可抑制Ras、MEK、pMEK及pERK的生理活性；並可抑制MMP2及MMP9蛋白表現。
從以上結果顯示，牡丹皮可以改善動脈血管平滑肌之增生。此作用係經由抑制MAPK pathway的活性及抑制MMP2及MMP9蛋白的表現。

Cerebral and cardiovascular diseases are mainly caused by the pathogenesis of arterial vascular smooth muscle. Paeonia suffruticosa Andr. (abbreviated as PSex)is a well-known traditional Chinese herbal medicine. Ancient Chinese medicine literatures have showed that various effects of this herb on human sickness such as reducing heat, promoting blood flow and eliminating stasis. Paeonol (2′-hydroxy-4′-methoxyacetophenone) is one of the main components extracted from PSex. Paeonol was reported to have multi-biological activites such as anti-inflammatory, anti-allergic, anti-tumor, anti-angiogenic, and anti-oxidative activities. In the present study, the effects and action mechanism of PSex and paeonol on vascular smooth muscle cells proliferation and migration were evaluated.
Results from our study revealed that PSex reduced hyperplasia in the mouse carotid ligation model. Low-dose (0.1 g/kg) or high-dose (0.2 g/kg) of PSex decreased the level of intima/media (I/M) ratio in 24 % and 37 % compared with the control group, respectively. PSex reduced PCNA positive cells in a dose-dependent manner and the inhibition rate was 35 % (0.1 g/kg) and 62 % (0.2 g/kg) compared with control. In wound healing assay and transwell migration assay. The results showed that PSex and paeonol extracts significantly inhibited platelet-derived growth factor (PDGF) induced A7r5 cells migration and proliferation. PSex and paeonol decreased Ras, MEK, p-MEK, p-ERK1/2 and MMP-2 and MMP-9protein level in western blotting analysis.
In conclusion, results from this study revealed that PSex inhibited
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carotid-ligation induced intimal hyperplasia; PSex and paeonol both inhibited PDGF –induced A7r5 cell proliferation and migration which might be via the inactivation of MMP2, MMP9, and MEK/ERK pathway

目 錄 I
致 謝 III
略字表 IV
圖目錄 VI
表目錄 VIII
中文摘要 IX
英文摘要 X
第一章 緒 言 1
第二章 總 論 2
第一節 牡丹皮之考察 2
第二節 牡丹皮成分 6
第三節 牡丹皮現代藥理相關研究 7
第四節 動脈硬化 9
第五節 血管形成手術 11
第六節 血管再狹窄 14
第七節 血管平滑肌細胞的遷移 16
第三章 實驗設計 19
第四章 實驗材料與方法 20
第一節 藥品試劑 20
第二節 常用儀器 22
第三節 藥材萃取及配製 23
第四節 牡丹皮之成分分析 24
第五節 牡丹酚的配製 25
第六節 牡丹皮萃取物對小鼠頸動脈結紮手術後所造成之內膜增生的作用影響 26
第七節 牡丹皮萃取物以及牡丹酚對於PDGF誘發血管平滑肌細胞增生和遷移的影響 30
第八節 牡丹皮萃取物及牡丹酚對PDGF誘發血管平滑肌細胞增生和遷移之作用機轉 34
第九節 統計分析 38
第五章 結 果 39
第一節 牡丹皮成分分析 39
第二節 牡丹皮萃取物對小鼠頸動脈結紮手術後所造成之內膜增生的影響 41
第三節 牡丹皮萃取物以及牡丹酚對PDGF誘發血管平滑肌細胞增生和遷移之影響 45
第四節 牡丹皮萃取物及牡丹酚對PDGF誘發血管平滑肌細胞增生和遷移之作用機轉 60
第六章 討 論 77
第七章 結 論 84
參考文獻 85

[1] A. Levitzki, PDGF receptor kinase inhibitors for the treatment of restenosis, Cardiovascular research, 65 (2005) 581-586.
[2] M. Joner, A.V. Finn, A. Farb, E.K. Mont, F.D. Kolodgie, E. Ladich, R. Kutys, K. Skorija, H.K. Gold, R. Virmani, Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk, Journal of the American College of Cardiology, 48 (2006) 193-202.
[3] W.S. Weintraub, The pathophysiology and burden of restenosis, The American journal of cardiology, 100 (2007) 3K-9K.
[4] J.B. Wu, N.N. Song, X.B. Wei, H.S. Guan, X.M. Zhang, Protective effects of paeonol on cultured rat hippocampal neurons against oxygen-glucose deprivation-induced injury, Journal of the neurological sciences, 264 (2008) 50-55.
[5] C.L. Hsieh, C.Y. Cheng, T.H. Tsai, I.H. Lin, C.H. Liu, S.Y. Chiang, J.G. Lin, C.J. Lao, N.Y. Tang, Paeonol reduced cerebral infarction involving the superoxide anion and microglia activation in ischemia-reperfusion injured rats, Journal of ethnopharmacology, 106 (2006) 208-215.
[6] M. Dai, X. Zhi, D. Peng, Q. Liu, [Inhibitory effect of paeonol on experimental atherosclerosis in quails], Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 24 (1999) 488-490, 512.
[7] M. Dai, Q.Y. Liu, C.G. Gu, H.Y. Zhang, [Inhibitory effect of paeonol on lipid peroxidational reaction and oxidational decorate of low density lipoprotein], Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 25 (2000) 625-627.
[8] Z.S. Al-Lebban, L.B. Corbeil, E.H. Coles, Rabbit pasteurellosis: induced disease and vaccination, American journal of veterinary research, 49
97
(1988) 312-316.
[9] G.S. Oh, H.O. Pae, B.M. Choi, S. Jeong, H. Oh, C.S. Oh, Y.D. Rho, D.H. Kim, M.K. Shin, H.T. Chung, Inhibitory effects of the root cortex of Paeonia suffruticosa on interleukin-8 and macrophage chemoattractant protein-1 secretions in U937 cells, Journal of ethnopharmacology, 84 (2003) 85-89.
[10] G. Ryu, E.K. Park, J.H. Joo, B.H. Lee, B.W. Choi, D.S. Jung, N.H. Lee, A new antioxidant monoterpene glycoside, alpha-benzoyloxypaeoniflorin from Paeonia suffruticosa, Archives of pharmacal research, 24 (2001) 105-108.
[11] M. Yoshikawa, E. Uchida, A. Kawaguchi, I. Kitagawa, J. Yamahara, Galloyl-oxypaeoniflorin, suffruticosides A, B, C, and D, five new antioxidative glycosides, and suffruticoside E, A paeonol glycoside, from Chinese moutan cortex, Chemical & pharmaceutical bulletin, 40 (1992) 2248-2250.
[12] R.B. An, H.C. Kim, S.H. Lee, G.S. Jeong, D.H. Sohn, H. Park, D.Y. Kwon, J.H. Lee, Y.C. Kim, A new monoterpene glycoside and antibacterial monoterpene glycosides from Paeonia suffruticosa, Archives of pharmacal research, 29 (2006) 815-820.
[13] 中華人民共和國國家藥典委員會, 中國藥典(一部), 化學工業出版社, (2005) 119.
[14] 戴新民, 中藥的藥理應用, (1983).
[15] Chiangsu New Medical College, Dictionary of Chinese Materia Medica, Shanghai Scientific and Technological Publishing Co, (1977) 1127-1130.
[16] T.K. Hwang, Handbook of Constituents and Pharmacology of Chinese Drugs; China Medical Scientific and Technological: Peiking, China,, (1994) 1040-1046.
[17] 行政院衛生署編印, 中華中藥典, (中華民國九十三年) 85.
98
[18] 魏．吳普等編, 清．孫星衍、孫馮翼, 神農本草經, 文光圖書公司, (1982) 162.
[19] 清．汪昂, 增補本草備要, 文光圖書公司, (1986).
[20] 蘇珊玉, 中藥銀杏與牡丹皮萃取物之神經保護作用在轉錄層次的實質機轉探討
The neuroprotective essence of extract from Chinese medicine Ginkgo biloba and Paeonia suffruticosa Andrews at the transcriptional level, 中國醫藥大學中醫學系博士論文, (民國九十九年).
[21] 趙文婉, 林璧鳳, 中藥材的免疫調節功能, 科學發展, 405 (2006) 55-63.
[22] 江蘇新醫學院, 中藥大辭典, 上海科學技術出版社, ( 1999 ).
[23] 中華人民共和國國家藥典委員會, 中華人民共和國藥典ㄧ部 化學工業出版社 (2005).
[24] 原思通, 醫用中藥飲片學, 中華人民共和國人民衛生出版社, (2001).
[25] 宋. 劉翰, 宋. 馬志, 謝文全, 林豐定, 重輯開寶重定本草, 中國醫藥學院中國要學研究所列印, (1998) 121-122.
[26] 宋. 掌禹錫, 那琦, 謝文全, 李一宏, 重輯嘉祐補柱神農本草, 中國醫藥學院中國藥學研究所印行, (1989) 93.
[27] 胡红宇, 杨. 郁, 于能江, 赵毅, 牡丹皮化學成份研究, 中國中藥雜誌, 31 (2006) 1793-1794.
[28] M.I. Cybulsky, M.A. Gimbrone, Jr., Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis, Science, 251 (1991) 788-791.
[29] M.I. Cybulsky, K. Iiyama, H. Li, S. Zhu, M. Chen, M. Iiyama, V. Davis, J.C. Gutierrez-Ramos, P.W. Connelly, D.S. Milstone, A major role for
99
VCAM-1, but not ICAM-1, in early atherosclerosis, The Journal of clinical investigation, 107 (2001) 1255-1262.
[30] M. Richardson, S.J. Hadcock, M. DeReske, M.I. Cybulsky, Increased expression in vivo of VCAM-1 and E-selectin by the aortic endothelium of normolipemic and hyperlipemic diabetic rabbits, Arteriosclerosis and thrombosis : a journal of vascular biology / American Heart Association, 14 (1994) 760-769.
[31] J. Fruebis, V. Gonzalez, M. Silvestre, W. Palinski, Effect of probucol treatment on gene expression of VCAM-1, MCP-1, and M-CSF in the aortic wall of LDL receptor-deficient rabbits during early atherogenesis, Arteriosclerosis, thrombosis, and vascular biology, 17 (1997) 1289-1302.
[32] M.J. Davies, J.L. Gordon, A.J. Gearing, R. Pigott, N. Woolf, D. Katz, A. Kyriakopoulos, The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis, The Journal of pathology, 171 (1993) 223-229.
[33] K.D. O''Brien, M.D. Allen, T.O. McDonald, A. Chait, J.M. Harlan, D. Fishbein, J. McCarty, M. Ferguson, K. Hudkins, C.D. Benjamin, et al., Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis, The Journal of clinical investigation, 92 (1993) 945-951.
[34] L.L. Pan, M. Dai, Paeonol from Paeonia suffruticosa prevents TNF-alpha-induced monocytic cell adhesion to rat aortic endothelial cells by suppression of VCAM-1 expression, Phytomedicine : international journal of phytotherapy and phytopharmacology, 16 (2009) 1027-1032.
[35] Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III; ATP-III). Final report., (Circulation 2002) 3143-3421.
100
[36] R. Ross, The pathogenesis of atherosclerosis: a perspective for the 1990s, Nature, 362 (1993) 801-809.
[37] A.V. Finn, M. Nakano, J. Narula, F.D. Kolodgie, R. Virmani, Concept of vulnerable/unstable plaque, Arteriosclerosis, thrombosis, and vascular biology, 30 (2010) 1282-1292.
[38] A.J. Lusis, Atherosclerosis, Nature, 407 (2000) 233-241.
[39] C. Landau, R.A. Lange, L.D. Hillis, Percutaneous transluminal coronary angioplasty, The New England journal of medicine, 330 (1994) 981-993.
[40] D.L. Fischman, M.B. Leon, D.S. Baim, R.A. Schatz, M.P. Savage, I. Penn, K. Detre, L. Veltri, D. Ricci, M. Nobuyoshi, et al., A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators, The New England journal of medicine, 331 (1994) 496-501.
[41] 謝宜璋, 長庚醫院心臟內科主治醫師, 心臟病居高不下！裝置塗藥支架就高枕無憂了嗎？, KingNet國家網路醫院, (2005).
[42] M.A. Gimbrone, Jr., T. Nagel, J.N. Topper, Biomechanical activation: an emerging paradigm in endothelial adhesion biology, The Journal of clinical investigation, 100 (1997) S61-65.
[43] H. Hanke, T. Strohschneider, M. Oberhoff, E. Betz, K.R. Karsch, Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty, Circulation research, 67 (1990) 651-659.
[44] J.G. Pickering, L. Weir, J. Jekanowski, M.A. Kearney, J.M. Isner, Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization, The Journal of clinical investigation, 91 (1993) 1469-1480.
101
[45] A.W. Clowes, M.A. Reidy, M.M. Clowes, Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium, Laboratory investigation; a journal of technical methods and pathology, 49 (1983) 327-333.
[46] A.W. Clowes, S.M. Schwartz, Significance of quiescent smooth muscle migration in the injured rat carotid artery, Circulation research, 56 (1985) 139-145.
[47] K. Malarkey, E.R. Chilvers, M.F. Lawson, R. Plevin, Stimulation by endothelin-1 of mitogen-activated protein kinases and DNA synthesis in bovine tracheal smooth muscle cells, British journal of pharmacology, 116 (1995) 2267-2273.
[48] M. Sundaresan, Z.X. Yu, V.J. Ferrans, K. Irani, T. Finkel, Requirement for generation of H2O2 for platelet-derived growth factor signal transduction, Science, 270 (1995) 296-299.
[49] T.F. Deuel, J.S. Huang, Platelet-derived growth factor. Structure, function, and roles in normal and transformed cells, The Journal of clinical investigation, 74 (1984) 669-676.
[50] E.G. Nabel, L. Shum, V.J. Pompili, Z.Y. Yang, H. San, H.B. Shu, S. Liptay, L. Gold, D. Gordon, R. Derynck, et al., Direct transfer of transforming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia, Proceedings of the National Academy of Sciences of the United States of America, 90 (1993) 10759-10763.
[51] M.B. Grant, T.J. Wargovich, E.A. Ellis, S. Caballero, M. Mansour, C.J. Pepine, Localization of insulin-like growth factor I and inhibition of coronary smooth muscle cell growth by somatostatin analogues in human coronary smooth muscle cells. A potential treatment for restenosis?, Circulation, 89 (1994) 1511-1517.
[52] G. Fager, Thrombin and proliferation of vascular smooth muscle cells, Circulation research, 77 (1995) 645-650.
102
[53] P.F. Li, R. Dietz, R. von Harsdorf, Differential effect of hydrogen peroxide and superoxide anion on apoptosis and proliferation of vascular smooth muscle cells, Circulation, 96 (1997) 3602-3609.
[54] 陳俊翰, 中藥成分magnolol及andrographolide對動脈粥狀硬化症之治療及其分子機轉, Molecular mechanisms and therapeutic effects of magnolol and andrographolide in atherosclerosis, 國防醫學院生命科學研究所博士論文, (2003).
[55] 周凌慧, 江美治, 小鼠頸動脈結紮模式中血管平滑肌細胞型態轉變過程之研究, 國立成功大學細胞生物與結剖學研究所碩士論文, (2007).
[56] A.T. Halka, N.J. Turner, A. Carter, J. Ghosh, M.O. Murphy, J.P. Kirton, C.M. Kielty, M.G. Walker, The effects of stretch on vascular smooth muscle cell phenotype in vitro, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology, 17 (2008) 98-102.
[57] L. Gu, Y. Okada, S.K. Clinton, C. Gerard, G.K. Sukhova, P. Libby, B.J. Rollins, Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice, Molecular cell, 2 (1998) 275-281.
[58] 蕭蓮如, 李彗禎, 龍葵萃取物抑制動脈硬化形成機轉之探討, 中山醫藥大學生化暨生物科技研究所碩士論文, (2008).
[59] M.C. Tsai, L. Chen, J. Zhou, Z. Tang, T.F. Hsu, Y. Wang, Y.T. Shih, H.H. Peng, N. Wang, Y. Guan, S. Chien, J.J. Chiu, Shear stress induces synthetic-to-contractile phenotypic modulation in smooth muscle cells via peroxisome proliferator-activated receptor alpha/delta activations by prostacyclin released by sheared endothelial cells, Circulation research, 105 (2009) 471-480.
[60] J. Thyberg, K. Blomgren, U. Hedin, M. Dryjski, Phenotypic modulation of smooth muscle cells during the formation of neointimal thickenings in the rat carotid artery after balloon injury: an electron-microscopic and
103
stereological study, Cell and tissue research, 281 (1995) 421-433.
[61] S.M. Schwartz, G.R. Campbell, J.H. Campbell, Replication of smooth muscle cells in vascular disease, Circulation research, 58 (1986) 427-444.
[62] B. Osterud, E. Bjorklid, Role of monocytes in atherogenesis, Physiological reviews, 83 (2003) 1069-1112.
[63] M.P. Bendeck, N. Zempo, A.W. Clowes, R.E. Galardy, M.A. Reidy, Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat, Circulation research, 75 (1994) 539-545.
[64] A. Luttun, E. Lutgens, A. Manderveld, K. Maris, D. Collen, P. Carmeliet, L. Moons, Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth, Circulation, 109 (2004) 1408-1414.
[65] C. Johnson, Z.S. Galis, Matrix metalloproteinase-2 and -9 differentially regulate smooth muscle cell migration and cell-mediated collagen organization, Arteriosclerosis, thrombosis, and vascular biology, 24 (2004) 54-60.
[66] M. Kuzuya, S. Kanda, T. Sasaki, N. Tamaya-Mori, X.W. Cheng, T. Itoh, S. Itohara, A. Iguchi, Deficiency of gelatinase a suppresses smooth muscle cell invasion and development of experimental intimal hyperplasia, Circulation, 108 (2003) 1375-1381.
[67] H.Y. Ju, S.C. Chen, K.J. Wu, H.C. Kuo, Y.C. Hseu, H. Ching, C.R. Wu, Antioxidant phenolic profile from ethyl acetate fraction of Fructus Ligustri Lucidi with protection against hydrogen peroxide-induced oxidative damage in SH-SY5Y cells, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 50 (2012) 492-502.
[68] Y.H. Li, H.C. Chung, S.L. Liu, T.H. Chao, J.C. Chen, A novel inhibitory
104
effect of Antrodia camphorata extract on vascular smooth muscle cell migration and neointima formation in mice, International heart journal, 50 (2009) 207-220.
[69] R. Tao, L. Lu, R. Zhang, J. Hu, J. Ni, W. Shen, Triptolide inhibits rat vascular smooth muscle cell proliferation and cell cycle progression via attenuation of ERK1/2 and Rb phosphorylation, Experimental and molecular pathology, 90 (2011) 137-142.
[70] R. Zargham, Preventing restenosis after angioplasty: a multistage approach, Clin Sci (Lond), 114 (2008) 257-264.
[71] J. Steffel, F.C. Tanner, Biological effects of drug-eluting stents in the coronary circulation, Herz, 32 (2007) 268-273.
[72] R. Beyar, Novel approaches to reduce restenosis, Annals of the New York Academy of Sciences, 1015 (2004) 367-378.
[73] C.M. Koon, K.S. Woo, P.C. Leung, K.P. Fung, Salviae Miltiorrhizae Radix and Puerariae Lobatae Radix herbal formula mediates anti-atherosclerosis by modulating key atherogenic events both in vascular smooth muscle cells and endothelial cells, Journal of ethnopharmacology, 138 (2011) 175-183.
[74] A. Kumar, V. Lindner, Remodeling with neointima formation in the mouse carotid artery after cessation of blood flow, Arteriosclerosis, thrombosis, and vascular biology, 17 (1997) 2238-2244.
[75] R.C. Braun-Dullaeus, M.J. Mann, V.J. Dzau, Cell cycle progression: new therapeutic target for vascular proliferative disease, Circulation, 98 (1998) 82-89.
[76] V. Sriram, C. Patterson, Cell cycle in vasculoproliferative diseases: potential interventions and routes of delivery, Circulation, 103 (2001) 2414-2419.
[77] Z. Kelman, PCNA: structure, functions and interactions, Oncogene, 14
105
(1997) 629-640.
[78] K.M. Abberton, N.H. Taylor, D.L. Healy, P.A. Rogers, Vascular smooth muscle cell proliferation in arterioles of the human endometrium, Hum Reprod, 14 (1999) 1072-1079.
[79] A.M. Holm, C.B. Andersen, S. Haunso, P.R. Hansen, ACE-inhibition promotes apoptosis after balloon injury of rat carotid arteries, Cardiovascular research, 45 (2000) 777-782.
[80] X. Wu, Q. Zhou, L. Huang, A. Sun, K. Wang, Y. Zou, J. Ge, Ageing-exaggerated proliferation of vascular smooth muscle cells is related to attenuation of Jagged1 expression in endothelial cells, Cardiovascular research, 77 (2008) 800-808.
[81] Y. Zhan, S. Kim, Y. Izumi, Y. Izumiya, T. Nakao, H. Miyazaki, H. Iwao, Role of JNK, p38, and ERK in platelet-derived growth factor-induced vascular proliferation, migration, and gene expression, Arteriosclerosis, thrombosis, and vascular biology, 23 (2003) 795-801.
[82] K.A. Kelly, J.R. Allport, A. Tsourkas, V.R. Shinde-Patil, L. Josephson, R. Weissleder, Detection of vascular adhesion molecule-1 expression using a novel multimodal nanoparticle, Circulation research, 96 (2005) 327-336.
[83] K. Bostrom, Osteopontin, a missing link in PDGF-induced smooth muscle cell migration, Cardiovascular research, 75 (2007) 634-635.
[84] K. Kingsley, J.L. Huff, W.L. Rust, K. Carroll, A.M. Martinez, M. Fitchmun, G.E. Plopper, ERK1/2 mediates PDGF-BB stimulated vascular smooth muscle cell proliferation and migration on laminin-5, Biochemical and biophysical research communications, 293 (2002) 1000-1006.
[85] G.A. Rosenberg, Matrix metalloproteinases and their multiple roles in neurodegenerative diseases, Lancet neurology, 8 (2009) 205-216.
106
[86] H.Y. Kim, S.H. Han, Matrix metalloproteinases in cerebral ischemia, J Clin Neurol, 2 (2006) 163-170.
[87] S.H. Heo, C.H. Cho, H.O. Kim, Y.H. Jo, K.S. Yoon, J.H. Lee, J.C. Park, K.C. Park, T.B. Ahn, K.C. Chung, S.S. Yoon, D.I. Chang, Plaque rupture is a determinant of vascular events in carotid artery atherosclerotic disease: involvement of matrix metalloproteinases 2 and 9, J Clin Neurol, 7 (2011) 69-76.
[88] R.R. Pauly, A. Passaniti, C. Bilato, R. Monticone, L. Cheng, N. Papadopoulos, Y.A. Gluzband, L. Smith, C. Weinstein, E.G. Lakatta, et al., Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation, Circulation research, 75 (1994) 41-54.
[89] Y.J. Li, J.X. Bao, J.W. Xu, F. Murad, K. Bian, Vascular dilation by paeonol--a mechanism study, Vascular pharmacology, 53 (2010) 169-176.
[90] M. Togni, S. Windecker, R. Cocchia, P. Wenaweser, S. Cook, M. Billinger, B. Meier, O.M. Hess, Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction, Journal of the American College of Cardiology, 46 (2005) 231-236.