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標題: 小蘗鹼抑制血小板衍生生長因子誘導大白鼠動脈血管平滑肌細胞增生及轉移之分子作用機轉
The molecular mechanisms of berberine-mediated inhibitory effect on platelet-derived growth factor-induced proliferation and migration in rat aortic smooth muscle cells
作者: 尹修竹
Yin, Sui-Chu
關鍵字: Berberine;小蘗鹼;Atherosclerosis;Restenosis;Rat vascular smooth muscle cells(RASMCs);Platelet-derived growth factor-BB (PDGF-BB);Proliferation;Migration;動脈粥樣硬化;血管再狹窄;血管平滑肌細胞;血小板衍生生長因子;細胞增生;細胞轉移
出版社: 生命科學院碩士在職專班
引用: 參考文獻 1. Rodgers, A., et al., Distribution of major health risks: findings from the Global Burden of Disease study. PLoS Med, 2004. 1(1): p. e27. 2. Murray, C.J., S.C. Kulkarni, and M. Ezzati, Understanding the coronary heart disease versus total cardiovascular mortality paradox: a method to enhance the comparability of cardiovascular death statistics in the United States. Circulation, 2006. 113(17): p. 2071-81. 3. Ross, R., The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature, 1993. 362(6423): p. 801-9. 4. Ross, R. and J.A. Glomset, Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science, 1973. 180(93): p. 1332-9. 5. Schwartz, S.M., D. deBlois, and E.R. O''Brien, The intima. Soil for atherosclerosis and restenosis. Circ Res, 1995. 77(3): p. 445-65. 6. Schwartz, S.M., Perspectives series: cell adhesion in vascular biology. Smooth muscle migration in atherosclerosis and restenosis. J Clin Invest, 1997. 99(12): p. 2814-6. 7. Chang, C.J., et al., Highly increased cell proliferation activity in the restenotic hemodialysis vascular access after percutaneous transluminal angioplasty: implication in prevention of restenosis. Am J Kidney Dis, 2004. 43(1): p. 74-84. 8. Hanke, H., et al., Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty. Circ Res, 1990. 67(3): p. 651-9. 9. Patterson, C., et al., Comparative effects of paclitaxel and rapamycin on smooth muscle migration and survival: role of AKT-dependent signaling. Arterioscler Thromb Vasc Biol, 2006. 26(7): p. 1473-80. 10. Popma, J.J. and E.J. Topol, Factors influencing restenosis after coronary angioplasty. Am J Med, 1990. 88(1N): p. 16N-24N. 11. Fischman, D.L., et al., A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med, 1994. 331(8): p. 496-501. 12. Serruys, P.W., et al., A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med, 1994. 331(8): p. 489-95. 13. Liu, M.W., G.S. Roubin, and S.B. King, 3rd, Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia. Circulation, 1989. 79(6): p. 1374-87. 14. Lowe, H.C., S.N. Oesterle, and L.M. Khachigian, Coronary in-stent restenosis: current status and future strategies. J Am Coll Cardiol, 2002. 39(2): p. 183-93. 15. Serruys, P.W., E. Regar, and A.J. Carter, Rapamycin eluting stent: the onset of a new era in interventional cardiology. Heart, 2002. 87(4): p. 305-7. 16. Grube, E., et al., TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation, 2003. 107(1): p. 38-42. 17. Ross, R., Cell biology of atherosclerosis. Annu Rev Physiol, 1995. 57: p. 791-804. 18. Dzau, V.J., R.C. Braun-Dullaeus, and D.G. Sedding, Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med, 2002. 8(11): p. 1249-56. 19. Voisard, R., et al., The in-vitro effect of antineoplastic agents on proliferative activity and cytoskeletal components of plaque-derived smooth-muscle cells from human coronary arteries. Coron Artery Dis, 1993. 4(10): p. 935-42. 20. March, K.L., et al., Biodegradable microspheres containing a colchicine analogue inhibit DNA synthesis in vascular smooth muscle cells. Circulation, 1994. 89(5): p. 1929-33. 21. Blagosklonny, M.V., et al., Paclitaxel induces primary and postmitotic G1 arrest in human arterial smooth muscle cells. Cell Cycle, 2004. 3(8): p. 1050-6. 22. Tanabe, H., et al., Double blockade of cell cycle progression by coptisine in vascular smooth muscle cells. Biochem Pharmacol, 2005. 70(8): p. 1176-84. 23. Stone, G.W., et al., A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med, 2004. 350(3): p. 221-31. 24. Ko, W.H., et al., Vasorelaxant and antiproliferative effects of berberine. Eur J Pharmacol, 2000. 399(2-3): p. 187-96. 25. Liang, K.W., et al., Berberine suppresses MEK/ERK-dependent Egr-1 signaling pathway and inhibits vascular smooth muscle cell regrowth after in vitro mechanical injury. Biochem Pharmacol, 2006. 71(6): p. 806-17. 26. Lau, C.W., et al., Cardiovascular actions of berberine. Cardiovasc Drug Rev, 2001. 19(3): p. 234-44. 27. Kong, W., et al., Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med, 2004. 10(12): p. 1344-51. 28. Pan, G.Y., et al., The antihyperglycaemic activity of berberine arises from a decrease of glucose absorption. Planta Med, 2003. 69(7): p. 632-6. 29. Leng, S.H., F.E. Lu, and L.J. Xu, Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion. Acta Pharmacol Sin, 2004. 25(4): p. 496-502. 30. Yin, J., et al., Effects of berberine on glucose metabolism in vitro. Metabolism, 2002. 51(11): p. 1439-43. 31. Glass, C.K. and J.L. Witztum, Atherosclerosis. the road ahead. Cell, 2001. 104(4): p. 503-16. 32. Ross, R., Atherosclerosis--an inflammatory disease. N Engl J Med, 1999. 340(2): p. 115-26. 33. Libby, P., Changing concepts of atherogenesis. J Intern Med, 2000. 247(3): p. 349-58. 34. Arroyo, L.H. and R.T. Lee, Mechanisms of plaque rupture: mechanical and biologic interactions. Cardiovasc Res, 1999. 41(2): p. 369-75. 35. Kornowski, R., et al., In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol, 1998. 31(1): p. 224-30. 36. Rajagopal, V. and S.G. Rockson, Coronary restenosis: a review of mechanisms and management. Am J Med, 2003. 115(7): p. 547-53. 37. Donners, M.M., et al., Inflammation and restenosis: implications for therapy. Ann Med, 2003. 35(7): p. 523-31. 38. McNamara, C.A., et al., Thrombin and vascular smooth muscle cell proliferation: implications for atherosclerosis and restenosis. Semin Thromb Hemost, 1996. 22(2): p. 139-44. 39. Libby, P., et al., A cascade model for restenosis. A special case of atherosclerosis progression. Circulation, 1992. 86(6 Suppl): p. III47-52. 40. Welt, F.G., et al., Neutrophil, not macrophage, infiltration precedes neointimal thickening in balloon-injured arteries. Arterioscler Thromb Vasc Biol, 2000. 20(12): p. 2553-8. 41. Lloyd, A.R. and J.J. Oppenheim, Poly''s lament: the neglected role of the polymorphonuclear neutrophil in the afferent limb of the immune response. Immunol Today, 1992. 13(5): p. 169-72. 42. Galis, Z.S. and J.J. Khatri, Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res, 2002. 90(3): p. 251-62. 43. Furman, C., et al., Systemic tissue inhibitor of metalloproteinase-1 gene delivery reduces neointimal hyperplasia in balloon-injured rat carotid artery. FEBS Lett, 2002. 531(2): p. 122-6. 44. Nagai, R., et al., Identification of two types of smooth muscle myosin heavy chain isoforms by cDNA cloning and immunoblot analysis. J Biol Chem, 1989. 264(17): p. 9734-7. 45. Sobue, K., K. Hayashi, and W. Nishida, Expressional regulation of smooth muscle cell-specific genes in association with phenotypic modulation. Mol Cell Biochem, 1999. 190(1-2): p. 105-18. 46. Schwartz, S.M., G.R. Campbell, and J.H. Campbell, Replication of smooth muscle cells in vascular disease. Circ Res, 1986. 58(4): p. 427-44. 47. Walker, L.N., et al., Production of platelet-derived growth factor-like molecules by cultured arterial smooth muscle cells accompanies proliferation after arterial injury. Proc Natl Acad Sci U S A, 1986. 83(19): p. 7311-5. 48. Orlandi, A., et al., Rat aortic smooth muscle cells isolated from different layers and at different times after endothelial denudation show distinct biological features in vitro. Arterioscler Thromb, 1994. 14(6): p. 982-9. 49. Myit, S., et al., Different growth properties of neointimal and medial smooth muscle cells in response to growth factors. J Vasc Res, 2003. 40(2): p. 97-104. 50. Bochaton-Piallat, M.L., et al., Phenotypic heterogeneity of rat arterial smooth muscle cell clones. Implications for the development of experimental intimal thickening. Arterioscler Thromb Vasc Biol, 1996. 16(6): p. 815-20. 51. Lemire, J.M., et al., Characterization of cloned aortic smooth muscle cells from young rats. Am J Pathol, 1994. 144(5): p. 1068-81. 52. Bochaton-Piallat, M.L., G. Gabbiani, and M.S. Pepper, Plasminogen activator expression in rat arterial smooth muscle cells depends on their phenotype and is modulated by cytokines. Circ Res, 1998. 82(10): p. 1086-93. 53. Heldin, C.H., B. Westermark, and A. Wasteson, Platelet-derived growth factor. Isolation by a large-scale procedure and analysis of subunit composition. Biochem J, 1981. 193(3): p. 907-13. 54. Li, X., et al., PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor. Nat Cell Biol, 2000. 2(5): p. 302-9. 55. Kazlauskas, A., A new member of an old family. Nat Cell Biol, 2000. 2(5): p. E78-9. 56. Bergsten, E., et al., PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat Cell Biol, 2001. 3(5): p. 512-6. 57. Gilbertson, D.G., et al., Platelet-derived growth factor C (PDGF-C), a novel growth factor that binds to PDGF alpha and beta receptor. J Biol Chem, 2001. 276(29): p. 27406-14. 58. LaRochelle, W.J., et al., PDGF-D, a new protease-activated growth factor. Nat Cell Biol, 2001. 3(5): p. 517-21. 59. Raines, E.W., PDGF and cardiovascular disease. Cytokine Growth Factor Rev, 2004. 15(4): p. 237-54. 60. Heldin, C.H. and B. Westermark, Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev, 1999. 79(4): p. 1283-316. 61. Kazlauskas, A., Receptor tyrosine kinases and their targets. Curr Opin Genet Dev, 1994. 4(1): p. 5-14. 62. Betsholtz, C., L. Karlsson, and P. Lindahl, Developmental roles of platelet-derived growth factors. Bioessays, 2001. 23(6): p. 494-507. 63. Seifert, R.A., et al., Two different subunits associate to create isoform-specific platelet-derived growth factor receptors. J Biol Chem, 1989. 264(15): p. 8771-8. 64. Fredriksson, L., H. Li, and U. Eriksson, The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev, 2004. 15(4): p. 197-204. 65. Rosenkranz, S. and A. Kazlauskas, Evidence for distinct signaling properties and biological responses induced by the PDGF receptor alpha and beta subtypes. Growth Factors, 1999. 16(3): p. 201-16. 66. Klinghoffer, R.A., et al., The two PDGF receptors maintain conserved signaling in vivo despite divergent embryological functions. Mol Cell, 2001. 7(2): p. 343-54. 67. Pawson, T. and J.D. Scott, Signaling through scaffold, anchoring, and adaptor proteins. Science, 1997. 278(5346): p. 2075-80. 68. Hoch, R.V. and P. Soriano, Roles of PDGF in animal development. Development, 2003. 130(20): p. 4769-84. 69. Jackson, C.L., et al., Role of endogenous platelet-derived growth factor in arterial smooth muscle cell migration after balloon catheter injury. Arterioscler Thromb, 1993. 13(8): p. 1218-26. 70. Fingerle, J., et al., Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery. Proc Natl Acad Sci U S A, 1989. 86(21): p. 8412-6. 71. Wiskirchen, J., et al., The effects of paclitaxel on the three phases of restenosis: smooth muscle cell proliferation, migration, and matrix formation: an in vitro study. Invest Radiol, 2004. 39(9): p. 565-71. 72. Jawien, A., et al., Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest, 1992. 89(2): p. 507-11. 73. Nabel, E.G., et al., Recombinant platelet-derived growth factor B gene expression in porcine arteries induce intimal hyperplasia in vivo. J Clin Invest, 1993. 91(4): p. 1822-9. 74. Ross, R., et al., Localization of PDGF-B protein in macrophages in all phases of atherogenesis. Science, 1990. 248(4958): p. 1009-12. 75. Wilcox, J.N., et al., Platelet-derived growth factor mRNA detection in human atherosclerotic plaques by in situ hybridization. J Clin Invest, 1988. 82(3): p. 1134-43. 76. Hart, C.E., et al., PDGFbeta receptor blockade inhibits intimal hyperplasia in the baboon. Circulation, 1999. 99(4): p. 564-9. 77. Yang, X., et al., Curcumin inhibits platelet-derived growth factor-stimulated vascular smooth muscle cell function and injury-induced neointima formation. Arterioscler Thromb Vasc Biol, 2006. 26(1): p. 85-90. 78. Schafer, K.A., The cell cycle: a review. Vet Pathol, 1998. 35(6): p. 461-78. 79. Sherr, C.J., Mammalian G1 cyclins. Cell, 1993. 73(6): p. 1059-65. 80. Hunter, T. and J. Pines, Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell, 1994. 79(4): p. 573-82. 81. Tyson, J.J., et al., Chemical kinetic theory: understanding cell-cycle regulation. Trends Biochem Sci, 1996. 21(3): p. 89-96. 82. Fang, F., et al., Dependence of cyclin E-CDK2 kinase activity on cell anchorage. Science, 1996. 271(5248): p. 499-502. 83. King, R.W., P.K. Jackson, and M.W. Kirschner, Mitosis in transition. Cell, 1994. 79(4): p. 563-71. 84. Booher, R.N., P.S. Holman, and A. Fattaey, Human Myt1 is a cell cycle-regulated kinase that inhibits Cdc2 but not Cdk2 activity. J Biol Chem, 1997. 272(35): p. 22300-6. 85. Fattaey, A. and R.N. Booher, Myt1: a Wee1-type kinase that phosphorylates Cdc2 on residue Thr14. Prog Cell Cycle Res, 1997. 3: p. 233-40. 86. Ohi, R. and K.L. Gould, Regulating the onset of mitosis. Curr Opin Cell Biol, 1999. 11(2): p. 267-73. 87. Pines, J., Cyclin-dependent kinase inhibitors: the age of crystals. Biochim Biophys Acta, 1997. 1332(1): p. M39-42. 88. Brooks, G., R.A. Poolman, and J.M. Li, Arresting developments in the cardiac myocyte cell cycle: role of cyclin-dependent kinase inhibitors. Cardiovasc Res, 1998. 39(2): p. 301-11. 89. McConnell, B.B., et al., Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes. Mol Cell Biol, 1999. 19(3): p. 1981-9. 90. Xiong, Y., et al., p21 is a universal inhibitor of cyclin kinases. Nature, 1993. 366(6456): p. 701-4. 91. Russo, A.A., et al., Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature, 1996. 382(6589): p. 325-31. 92. Liew, C.T., et al., High frequency of p16INK4A gene alterations in hepatocellular carcinoma. Oncogene, 1999. 18(3): p. 789-95. 93. Hartwell, L.H. and T.A. Weinert, Checkpoints: controls that ensure the order of cell cycle events. Science, 1989. 246(4930): p. 629-34. 94. Koepp, D.M., J.W. Harper, and S.J. Elledge, How the cyclin became a cyclin: regulated proteolysis in the cell cycle. Cell, 1999. 97(4): p. 431-4. 95. Pietenpol, J.A. and Z.A. Stewart, Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis. Toxicology, 2002. 181-182: p. 475-81. 96. Perlman, H., et al., GATA-6 induces p21(Cip1) expression and G1 cell cycle arrest. J Biol Chem, 1998. 273(22): p. 13713-8. 97. Smith, R.C., et al., p21CIP1-mediated inhibition of cell proliferation by overexpression of the gax homeodomain gene. Genes Dev, 1997. 11(13): p. 1674-89. 98. Kastan, M.B., C.E. Canman, and C.J. Leonard, P53, cell cycle control and apoptosis: implications for cancer. Cancer Metastasis Rev, 1995. 14(1): p. 3-15. 99. Levine, A.J., p53, the cellular gatekeeper for growth and division. Cell, 1997. 88(3): p. 323-31. 100. Prives, C. and P.A. Hall, The p53 pathway. J Pathol, 1999. 187(1): p. 112-26. 101. May, P. and E. May, Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene, 1999. 18(53): p. 7621-36. 102. Liu, H., et al., New roles for the RB tumor suppressor protein. Curr Opin Genet Dev, 2004. 14(1): p. 55-64. 103. Tanner, F.C., et al., Expression of cyclin-dependent kinase inhibitors in vascular disease. Circ Res, 1998. 82(3): p. 396-403. 104. Wei, G.L., et al., Temporally and spatially coordinated expression of cell cycle regulatory factors after angioplasty. Circ Res, 1997. 80(3): p. 418-26. 105. Kuo, C.L., C.W. Chi, and T.Y. Liu, The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett, 2004. 203(2): p. 127-37. 106. Amin, A.H., T.V. Subbaiah, and K.M. Abbasi, Berberine sulfate: antimicrobial activity, bioassay, and mode of action. Can J Microbiol, 1969. 15(9): p. 1067-76. 107. Jantova, S., et al., Effect of berberine on proliferation, cell cycle and apoptosis in HeLa and L1210 cells. J Pharm Pharmacol, 2003. 55(8): p. 1143-9. 108. Anis, K.V., N.V. Rajeshkumar, and R. Kuttan, Inhibition of chemical carcinogenesis by berberine in rats and mice. J Pharm Pharmacol, 2001. 53(5): p. 763-8. 109. Lee, S., et al., Berberine inhibits rat vascular smooth muscle cell proliferation and migration in vitro and improves neointima formation after balloon injury in vivo. Berberine improves neointima formation in a rat model. Atherosclerosis, 2006. 186(1): p. 29-37. 110. Cho, B.J., et al., Berberine inhibits the production of lysophosphatidylcholine-induced reactive oxygen species and the ERK1/2 pathway in vascular smooth muscle cells. Mol Cells, 2005. 20(3): p. 429-34. 111. Takuwa, Y., [Rho-Rho kinase pathway]. Nippon Rinsho, 2004. 62(1): p. 43-8. 112. Ridley, A.J., et al., Cell migration: integrating signals from front to back. Science, 2003. 302(5651): p. 1704-9. 113. Hall, A., Rho GTPases and the actin cytoskeleton. Science, 1998. 279(5350): p. 509-14. 114. Liu, B., et al., The signaling protein Rho is necessary for vascular smooth muscle migration and survival but not for proliferation. Surgery, 2002. 132(2): p. 317-25. 115. Kaibuchi, K., S. Kuroda, and M. Amano, Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Annu Rev Biochem, 1999. 68: p. 459-86. 116. Croft, D.R. and M.F. Olson, The Rho GTPase effector ROCK regulates cyclin A, cyclin D1, and p27Kip1 levels by distinct mechanisms. Mol Cell Biol, 2006. 26(12): p. 4612-27. 117. Olson, M.F., A. Ashworth, and A. Hall, An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science, 1995. 269(5228): p. 1270-2. 118. Olson, M.F., H.F. Paterson, and C.J. Marshall, Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1. Nature, 1998. 394(6690): p. 295-9. 119. Weber, J.D., et al., Ras-stimulated extracellular signal-related kinase 1 and RhoA activities coordinate platelet-derived growth factor-induced G1 progression through the independent regulation of cyclin D1 and p27. J Biol Chem, 1997. 272(52): p. 32966-71. 120. Blaschke, F., D. Bruemmer, and R.E. Law, Egr-1 is a major vascular pathogenic transcription factor in atherosclerosis and restenosis. Rev Endocr Metab Disord, 2004. 5(3): p. 249-54. 121. Adhikari, N., et al., Transcription factor and kinase-mediated signaling in atherosclerosis and vascular injury. Curr Atheroscler Rep, 2006. 8(3): p. 252-60. 122. Khachigian, L.M., Early growth response-1 in cardiovascular pathobiology. Circ Res, 2006. 98(2): p. 186-91. 123. Braddock, M., The transcription factor Egr-1: a potential drug in wound healing and tissue repair. Ann Med, 2001. 33(5): p. 313-8. 124. Santiago, F.S., et al., Early growth response factor-1 induction by injury is triggered by release and paracrine activation by fibroblast growth factor-2. Am J Pathol, 1999. 154(3): p. 937-44. 125. Gashler, A.L., S. Swaminathan, and V.P. Sukhatme, A novel repression module, an extensive activation domain, and a bipartite nuclear localization signal defined in the immediate-early transcription factor Egr-1. Mol Cell Biol, 1993. 13(8): p. 4556-71. 126. Cao, X.M., et al., Identification and characterization of the Egr-1 gene product, a DNA-binding zinc finger protein induced by differentiation and growth signals. Mol Cell Biol, 1990. 10(5): p. 1931-9. 127. Thiel, G. and G. Cibelli, Regulation of life and death by the zinc finger transcription factor Egr-1. J Cell Physiol, 2002. 193(3): p. 287-92. 128. Kaufmann, K. and G. Thiel, Epidermal growth factor and thrombin induced proliferation of immortalized human keratinocytes is coupled to the synthesis of Egr-1, a zinc finger transcriptional regulator. J Cell Biochem, 2002. 85(2): p. 381-91. 129. Hardie, D.G. and D. Carling, The AMP-activated protein kinase--fuel gauge of the mammalian cell? Eur J Biochem, 1997. 246(2): p. 259-73. 130. Hardie, D.G., D. Carling, and M. Carlson, The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu Rev Biochem, 1998. 67: p. 821-55. 131. Ingebritsen, T.S., et al., Reversible modulation of the activities of both liver microsomal hydroxymethylglutaryl coenzyme A reductase and its inactivating enzyme. Evidence for regulation by phosphorylation-dephosphorylation. Biochem Biophys Res Commun, 1978. 81(4): p. 1268-77. 132. Weekes, J., et al., Activation of rat liver AMP-activated protein kinase by kinase kinase in a purified, reconstituted system. Effects of AMP and AMP analogues. Eur J Biochem, 1994. 219(3): p. 751-7. 133. Carling, D., et al., Purification and characterization of the AMP-activated protein kinase. Copurification of acetyl-CoA carboxylase kinase and 3-hydroxy-3-methylglutaryl-CoA reductase kinase activities. Eur J Biochem, 1989. 186(1-2): p. 129-36. 134. Carling, D., V.A. Zammit, and D.G. Hardie, A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett, 1987. 223(2): p. 217-22. 135. Ferrer, A., et al., Activation of rat liver cytosolic 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase by adenosine 5''-monophosphate. Biochem Biophys Res Commun, 1985. 132(2): p. 497-504. 136. Moore, F., J. Weekes, and D.G. Hardie, Evidence that AMP triggers phosphorylation as well as direct allosteric activation of rat liver AMP-activated protein kinase. A sensitive mechanism to protect the cell against ATP depletion. Eur J Biochem, 1991. 199(3): p. 691-7. 137. Igata, M., et al., Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression. Circ Res, 2005. 97(8): p. 837-44. 138. Nagata, D., et al., AMP-activated protein kinase inhibits angiotensin II-stimulated vascular smooth muscle cell proliferation. Circulation, 2004. 110(4): p. 444-51. 139. Motoshima, H., et al., AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol, 2006. 574(Pt 1): p. 63-71. 140. Rattan, R., et al., 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. J Biol Chem, 2005. 280(47): p. 39582-93. 141. Miano, J.M., et al., Retinoid receptor expression and all-trans retinoic acid-mediated growth inhibition in vascular smooth muscle cells. Circulation, 1996. 93(10): p. 1886-95. 142. Inui, H., et al., Transduction of mitogenic activity of platelet-derived growth factor (PDGF) AB by PDGF-beta receptor without participation of PDGF-alpha receptor in vascular smooth muscle cells. J Biol Chem, 1993. 268(23): p. 17045-50. 143. Kocan, R.M., N.S. Moss, and E.P. Benditt, Human arterial wall cells and tissues in culture. Methods Cell Biol, 1980. 21A: p. 153-66. 144. Gunther, S., M.A. Gimbrone, Jr., and R.W. Alexander, Identification and characterization of the high affinity vascular angiotensin II receptor in rat mesenteric artery. Circ Res, 1980. 47(2): p. 278-86. 145. Granada, J.F., et al., Single perivascular delivery of mitomycin C stimulates p21 expression and inhibits neointima formation in rat arteries. Arterioscler Thromb Vasc Biol, 2005. 25(11): p. 2343-8. 146. Fuster, V., Lewis A. Conner Memorial Lecture. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation, 1994. 90(4): p. 2126-46. 147. George, S.J., A. Williams, and A.C. Newby, An essential role for platelet-derived growth factor in neointima formation in human saphenous vein in vitro. Atherosclerosis, 1996. 120(1-2): p. 227-40. 148. Burgess, W.H. and T. Maciag, The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem, 1989. 58: p. 575-606. 149. Schwartz, R.S., D.R. Holmes, Jr., and E.J. Topol, The restenosis paradigm revisited: an alternative proposal for cellular mechanisms. J Am Coll Cardiol, 1992. 20(5): p. 1284-93. 150. Andres, V. and C. Castro, Antiproliferative strategies for the treatment of vascular proliferative disease. Curr Vasc Pharmacol, 2003. 1(1): p. 85-98. 151. Moses, J.W., et al., Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med, 2003. 349(14): p. 1315-23. 152. Kuo, C.L., C.C. Chou, and B.Y. Yung, Berberine complexes with DNA in the berberine-induced apoptosis in human leukemic HL-60 cells. Cancer Lett, 1995. 93(2): p. 193-200. 153. Li, X.K., et al., Huanglian, A chinese herbal extract, inhibits cell growth by suppressing the expression of cyclin B1 and inhibiting CDC2 kinase activity in human cancer cells. Mol Pharmacol, 2000. 58(6): p. 1287-93. 154. Ferns, G.A., et al., Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science, 1991. 253(5024): p. 1129-32. 155. Seger, R. and E.G. Krebs, The MAPK signaling cascade. Faseb J, 1995. 9(9): p. 726-35. 156. Liu, B., M. Fisher, and P. Groves, Down-regulation of the ERK1 and ERK2 mitogen-activated protein kinases using antisense oligonucleotides inhibits intimal hyperplasia in a porcine model of coronary balloon angioplasty. Cardiovasc Res, 2002. 54(3): p. 640-8. 157. Davis, R.J., The mitogen-activated protein kinase signal transduction pathway. J Biol Chem, 1993. 268(20): p. 14553-6. 158. Nishida, E. and Y. Gotoh, The MAP kinase cascade is essential for diverse signal transduction pathways. Trends Biochem Sci, 1993. 18(4): p. 128-31. 159. Lundberg, M.S., et al., Regulation of vascular smooth muscle migration by mitogen-activated protein kinase and calcium/calmodulin-dependent protein kinase II signaling pathways. J Mol Cell Cardiol, 1998. 30(11): p. 2377-89. 160. Graf, K., et al., Mitogen-activated protein kinase activation is involved in platelet-derived growth factor-directed migration by vascular smooth muscle cells. Hypertension, 1997. 29(1 Pt 2): p. 334-9. 161. Claesson-Welsh, L., Platelet-derived growth factor receptor signals. J Biol Chem, 1994. 269(51): p. 32023-6. 162. Graves, L.M., et al., Platelet-derived growth factor stimulates protein kinase A through a mitogen-activated protein kinase-dependent pathway in human arterial smooth muscle cells. J Biol Chem, 1996. 271(1): p. 505-11. 163. Jiang, B., et al., Differential effects of platelet-derived growth factor isotypes on human smooth muscle cell proliferation and migration are mediated by distinct signaling pathways. Surgery, 1996. 120(2): p. 427-31; discussion 432. 164. Lavoie, J.N., et al., Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem, 1996. 271(34): p. 20608-16. 165. Resnitzky, D., et al., Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. Mol Cell Biol, 1994. 14(3): p. 1669-79. 166. Chang, M.W., et al., Adenovirus-mediated over-expression of the cyclin/cyclin-dependent kinase inhibitor, p21 inhibits vascular smooth muscle cell proliferation and neointima formation in the rat carotid artery model of balloon angioplasty. J Clin Invest, 1995. 96(5): p. 2260-8. 167. Weiss, R.H., A. Joo, and C. Randour, p21(Waf1/Cip1) is an assembly factor required for platelet-derived growth factor-induced vascular smooth muscle cell proliferation. J Biol Chem, 2000. 275(14): p. 10285-90. 168. Yang, Z.Y., et al., Role of the p21 cyclin-dependent kinase inhibitor in limiting intimal cell proliferation in response to arterial injury. Proc Natl Acad Sci U S A, 1996. 93(15): p. 7905-10. 169. Ishikura, K., et al., Trapidil inhibits platelet-derived growth factor-induced migration via protein kinase A and RhoA/Rho-associated kinase in rat vascular smooth muscle cells. Eur J Pharmacol, 2005. 515(1-3): p. 28-33. 170. Massberg, S., et al., Activated platelets trigger an inflammatory response and enhance migration of aortic smooth muscle cells. Thromb Res, 2003. 110(4): p. 187-94. 171. Takai, Y., et al., Rho as a regulator of the cytoskeleton. Trends Biochem Sci, 1995. 20(6): p. 227-31. 172. Seasholtz, T.M., et al., Rho and Rho kinase mediate thrombin-stimulated vascular smooth muscle cell DNA synthesis and migration. Circ Res, 1999. 84(10): p. 1186-93. 173. Etienne-Manneville, S. and A. Hall, Rho GTPases in cell biology. Nature, 2002. 420(6916): p. 629-35. 174. Lee, Y.S., et al., Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes, 2006. 55(8): p. 2256-64. 175. Gashler, A. and V.P. Sukhatme, Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors. Prog Nucleic Acid Res Mol Biol, 1995. 50: p. 191-224. 176. Kaufmann, K. and G. Thiel, Epidermal growth factor and platelet-derived growth factor induce expression of Egr-1, a zinc finger transcription factor, in human malignant glioma cells. J Neurol Sci, 2001. 189(1-2): p. 83-91.

血管平滑肌細胞(vascular smooth muscle cells, VSMCs)的異常增生(proliferation)及轉移(migration)會造成血管內膜(intima)增厚,是導致心血管疾病如動脈粥樣硬化(atherosclerosis)、靜脈移植栓塞(vein graft occlusion)和經皮冠狀動脈腔內血管造形術(percutaneous transluminal coronary angioplasty, PTCA)之後血管再狹窄(restenosis)發生的關鍵原因。在臨床上,這些疾病僅能藉由藥物控制或外科手術來進行治療,但往往在數月或數年之後,患者又會再度復發,到目前為止仍無法有效治療,因此尋找新的治療藥物及治療方法為當務之急。當血管內膜受到損傷時,血管內皮細胞、血管平滑肌細胞、血小板及巨嗜細胞均會分泌大量的生長因子如血小板衍生生長因子(platelet-derived growth factor, PDGF)、纖維母細胞生長因子(basic fibroblast growth factor, bFGF)、類胰島素生長因子(insulin-like growth factor, IGF)和血管收縮素(angiotensin Ⅱ, Ang Ⅱ)等等,來誘導血管平滑肌細胞的增生及轉移,進而造成新生血管內膜(neointima)增厚及血管再狹窄。小蘗鹼(berberine)是中草藥黃連(Coptis chinensis)的主成分之一,屬於異喹啉類(isoquinoline)植物性生物鹼,具有降膽固醇、降血壓、降血糖、抑制細胞增生、抗癌、消炎解毒、抗菌、殺蟲等等功效。文獻上曾報導小檗鹼具有抑制血管平滑肌細胞增生及轉移的作用,但其確切的調控機轉則仍未有定論。在我們之前的研究中曾經證實體外培養的血管平滑肌細胞受到機械性損傷後,會釋出大量的PDGF並且促進細胞的增生,而此現象會受到小蘗鹼所抑制。本研究因此直接以PDGF-BB誘導體外培養的血管平滑肌細胞之增生及轉移,進而探討小蘗鹼抑制此現象的作用機轉。結果發現,小蘗鹼可透過將細胞週期停滯在G0-G1期而無法進入S期來抑制PDGF-BB所誘導血管平滑肌細胞的增生。經由顯微鏡下觀察及細胞計數的結果發現,小檗鹼確實可以3、10、30及100 uM濃度相關性地抑制PDGF-BB所誘導血管平滑肌細胞的增生。透過西方墨點轉漬分析(Western blotting assay)證實在此過程中,PDGF-BB活化了MEK1/2(mitogen-activated protein kinase 1/2)、ERK1/2(extracellular signal-regulated kinase 1/2)、Akt,並且增加Cyclin-D1、-D3的表現量及Cdk (cyclin dependent kinase)2、4的活性;藉由半定量RT-PCR分析(semi-quantitative reverse-transcription PCR assay)證實PDGF-BB在核酸層次對血管平滑肌細胞即具有調控作用。而小蘗鹼則顯著地抑制PDGF-BB所誘導MEK1/2、ERK1/2、Akt的活化及Cyclin-D1、-D3、Cdk2、4的表現量,並增加Cdk inhibitor p21CIP1/WAF1的表現量。Cdk inhibitor p21CIP1/WAF1的表現量增加可能是由於小蘗鹼活化AMP-activated protein kinase(adenosine monophosphate-activated protein kinase, AMPK)造成p53的磷酸化所致。Wound healing assay與Boyden chamber assay證實小蘗鹼可阻止PDGF-BB所誘導血管平滑肌細胞的轉移。進一步透過分析發現PDGF-BB增加Ras、Rac1、Cdc42的活性,同時此活性也受到小蘗鹼所抑制。由實驗結果得知小蘗鹼阻斷PDGF-BB所活化Ras/MEK/ERK-Akt路徑來抑制血管平滑肌細胞的增生;阻斷PDGF-BB所活化Rac/Cdc42路徑來抑制血管平滑肌細胞的轉移。因此,藉由中草藥小蘗鹼抑制血管平滑肌細胞的增生及轉移的特性,將有助於未來開發新藥來預防及治療心血管疾病。


Deregulated proliferation and migration of vascular smooth muscle cells (VSMCs)induced neointima formation plays an important role in many coronary diseases including the pathogenesis of atherosclerosis, vein graft occlusion and post-angioplasty restenosis. Clinically up to date, there were still no effective therapy to cure such vascular diseases. Therefore, it is very imperative to find new drugs and strategies to treat such diseases. Platelet-derived growth factor (PDGF) is released from VSMCs, vascular endothelial cells (VECs), platelets or macrophages after percutaneous coronary intervention and is strongly associated with neointima formation and restenosis. Berberine, an isoquinolinal plant alkaloid isolated from a well-known Chinese medicinal herb Huanglian (Coptis chinensis), has cholesterol-lowering, hypotensive, cell-growth inhibition, anti-cancer, anti-inflammatory and anti-microbial effects. Berberine could inhibit VSMCs proliferation and migration, yet the exact mechanisms are still unknown. Our previous results showed that berberine is capable of inhibiting cell growth and endogenous PDGF synthesis in rat aortic vascular smooth muscle cells(RASMCs)after in vitro mechanical injury. In the preceeding study, we explore the effects of berberine on RASMCs growth, migration, and downstream signaling events after exogenous PDGF-BB stimulation in vitro in order to mimic a post-angioplasty PDGF shedding condition. By flow cytometry analysis, our results showed that berberine could dose-dependently inhibit PDGF-BB-induced proliferation and cause cell cycle arrest at G0-G1 phase. Western blot analysis showed that PDGF-BB stimulated the activation of MEK1/2 (mitogen-activated protein kinase 1/2), ERK1/2 (extracellular signal-regulated kinase 1/2), Akt, and increased the expression of Cyclin-D1, -D3 and Cdk (cyclin dependent kinase)2, 4, and down-regulated Cdk inhibitor p21CIP1/WAF1expression. Semi-quantitative reverse-transcription PCR (RT-PCR) assay further confirmed the increase in cyclin-D1, -D3 and CDK2, 4 expression at transcriptional level. Berberine increased the activity of AMPK (adenosine monophosphate-activated protein kinase, AMP-activated protein kinase), which led to phosphorylation activation of p53 and up-regulated protein level of Cdk inhibitor p21CIP1/WAF1. Berberine significantly suppressed MEK 1/2, ERK1/2, Akt activation and cyclin-D1, -D3 and Cdk2, 4 expression after PDGF-BB stimulation. Moreover, wound healing assay and Boyden chamber assay showed that berberine prevented PDGF-BB-induced migration in RASMCs. Furthermore, from pull-down assay demonstrated stimulation of RASMCs with PDGF-BB led to a transient increase in Ras, Rac1, Cdc42 activities; however, pretreatment with berberine for 24 h significantly inhibited PDGF-BB-induced Ras, Rac1, Cdc42 activation. These data suggest that berberine inhibited PDGF-BB-induced RASMCs growth via activating the AMPK/p53/p21CIP1/WAF1 signaling, inactivating the Ras/MEK/ ERK- Akt pathway, and suppress PDGF-BB-stimulated migration via inhibition of Rac/Cdc42. These observations offer a molecular explanation for the anti-proliferative and anti-migratory properties of berberine, and suggest that this drug may potentially be used in treating disorders due to unproperly SMCs proliferation.
其他識別: U0005-1408200710091600
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