臺灣博碩士論文加值系統

本篇論文主要研究黃芩的主成分baicalein和茵陳的主成分esculetin對大鼠血管平滑肌細胞生長調控的影響。我們使用[3H]thymidine攝入量和MTT 法來研究，結果發現baicalein和esculetin對於血清所引起的DNA合成及細胞增生皆有抑制作用，且呈現濃度相依性的關係；而且即使在baicalein和esculetin的高濃度（100M）下，對於細胞存活率和lactate dehydrogenase（LDH）的釋放情形皆無顯著影響，因此我們認為baicalein和esculetin抑制血管平滑肌增生的作用並非經由造成細胞毒性而來。本篇探討baicalein和esculetin對血清所誘發的ERKs和原致癌基因（c-myc、c-jun和c-fos）之mRNA表現量的影響；由實驗結果得知，baicalein、esculetin和PD98059皆能顯著地抑制血清所引起之ERK1/2的活化；baicalein會明顯抑制c-myc和c-jun，但對c-fos之mRNA表現量不具影響；esculetin則會明顯抑制c-jun和c-fos，但對c-myc之mRNA表現量不具影響；而PD98059對此三種原致癌基因之mRNA的表現量皆有抑制作用。由這些實驗結果顯示baicalein、esculetin和PD98059是經由抑制ERKs所參與的訊息傳遞路徑來抑制細胞增生，然而他們對原致癌基因（c-myc、c-jun和c-fos）的調控具有不同的選擇性。在本篇實驗中，我們也去了解NF-kB相關的訊息傳遞路徑參與的情形；由實驗結果得知，baicalein、esculetin和PD98059皆會明顯抑制血清所誘發之IkBa的磷酸化作用及降解作用，然後去抑制NF-kB轉錄因子的活化。我們也進一步地去觀察藥物對cyclin D1的影響，baicalein和esculetin會顯著地抑制血清所引起之cyclin D1的表現；PD98059則無此抑制作用。為了解釋其中矛盾的情形，我們也去觀察這些藥物對PI3 kinase訊息傳遞路徑的影響；由實驗結果發現，baicalein和esculetin會明顯地抑制血清所引起之Akt磷酸化的作用，顯示它們會去影響PI3 kinase的訊息傳遞路徑；這也解釋了baicalein和esculetin會抑制血清所誘發之cyclin D1表現的原因。此外，我們使用lipoxygenase的代謝產物12-hydroxyeicosatetraenoic acid和15- hydroxyeicosatetraenoic acid來觀察在baicalein和esculetin的作用中，lipoxygenase的抑制作用扮演怎樣的角色；結果發現12-hydroxyeicosatetraenoic acid 和15- hydroxyeicosatetraenoic acid並不會有效地去改變baicalein和esculetin的作用，所以我們認為lipoxygenase的抑制作用並沒有參與在baicalein和esculetin抗增生的機制中。綜合以上所述，我們認為baicalein和esculetin之抗增生作用主要是透過抑制多重上游訊息傳遞，例如ERKs的活化、Akt的磷酸化和NF-kB轉錄因子的活性，接著去抑制原致癌基因（c-myc、c-jun和c-fos）mRNA之表現及細胞週期進行的下游訊息。

In our present work, we have examined the effects of baicalein and esculetin on the regulation of cell growth in rat vascular smooth muscle cells (VSMCs). Both baicalein and esculetin inhibited serum-induced DNA synthesis and cell proliferation in a concentration-dependent manner using [3H]thymidine incorporation and MTT assay methods. Furthermore, even at a high concentration of 100 M they still showed little influence on the cell viability or release of lactate dehydrogenase, suggesting that they exhibited the antiproliferative other than cytotoxic effect in rat VSMCs. We then determined several cellular events after the treatment of serum such as the activation of ERK-1 and -2 as well as the mRNA expressions of c-fos, c-myc, and c-jun in the presence of baicalein, esculetin, or the comparative agents. The results showed that baicalein, esculetin, and PD98059 significantly inhibited the ERKs activation to serum challenge. Baicalein markedly inhibited the c-myc and c-jun, rather than c-fos mRNA expression; esculetin, the c-jun and c-fos, but not c-myc, and PD98059, all of these three mRNA expression. These data revealed that all of these three agents inhibited the cell proliferation via the suppression of ERKs-involved pathway. However, they showed different regulation on the expressions of c-myc, c-jun, and c-fos. We also determined the NF-kB-related signaling pathway in the present study. The results demonstrated that baicalein, esculetin, and PD98059 all profoundly inhibited the serum-induced phosphorylation and degradation of IkBa, and then suppressed the NF-kB DNA-binding activity. Furthermore, baicalein and esculetin other than PD98059 significantly inhibited serum-induced increase of cyclin D1 expression and the following progression of cell cycle. To further elucidate this discrepancy, we also examined their effects on the PI-3 kinase signaling pathway. It showed that both baicalein and esculetin markedly inhibited serum-induced Akt phosphorylation revealing their inhibition on PI-3 kinase signaling pathway. This also explains their inhibitory effects on the increase of cyclin D1 expression induced by serum. The lipoxygenase metabolites, 12-hydroxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid, were used in this study to investigate the role of lipoxygenase inhibition in baicalein- and esculetin-mediated effects. However, 12-hydroxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid could not effectively alter the actions to baicalein and esculetin suggesting lipoxygenase inhibition was not involved. In summary, both baicalein and esculetin may exhibit their anti-proliferative effects via the inhibition on several upstream events, such as ERKs activation, Akt phosphorylation, and NF-kB DNA-binding activity, the subsequent suppression on c-myc, c-jun, and c-fos protooncogenes, and the inhibition on the downstream signals of cell cycle progression.

縮寫表---------------------------------------------------------1
中文摘要-------------------------------------------------------3
英文摘要-------------------------------------------------------5
第一章 緒論----------------------------------------------------7
一、文獻回顧--------------------------------------------7
二、研究動機和目的-------------------------------------18
第二章 材料與方法---------------------------------------------22
第三章 結果---------------------------------------------------34
一、藥物對細胞功能的影響-------------------------------34
二、藥物抑制細胞增生作用之訊息傳遞---------------------35
三、藥物對轉錄因子活化的影響---------------------------37
四、藥物對細胞生長週期的影響---------------------------40
五、 LIPOXYGENASE的代謝產物12-HETE和15-HETE
對藥物抑制細胞增生機制之參與----------------------42
第四章 討論---------------------------------------------------44
圖表----------------------------------------------------------52
參考文獻------------------------------------------------------87

Angel, P. and Karin, M. (1991) The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochimica et Biophysica Acta. 1072:129-57.
Axelrod, J., Burch, RM. and Jelsema, CL. (1988) Receptor-mediated activation of phospholipase A2 via GTP-binding proteins: arachidonic acid and its metabolites as second messengers. Trends in Neurosciences 11:117-23.
Baeuerle, PA. and Henkel, T. (1994) Function and activation of NF-kappa B in the immune system. Annual Review of Immunology 12:141-79.
Banskota, NK., Taub, R., Zellner, K. and King, GL. (1989) Insulin, insulin-like growth factor I and platelet-derived growth factor interact additively in the induction of the protooncogene c-myc and cellular proliferation in cultured bovine aortic smooth muscle cells. Molecular Endocrinology 3:1183-90.
Barath, P., Fishbein, MC., Cao, J., Berenson, J., Helfant, RH. and Forrester, JS. (1990) Tumor necrosis factor gene expression in human vascular intimal smooth muscle cells detected by in situ hybridization. American Journal of Pathology 137:503-9.
Bauters, C. and Isner, JM. (1997) The biology of restenosis. Progress in Cardiovascular Diseases 40:107-16.
Bennett, MR., Anglin, S., McEwan, JR., Jagoe, R., Newby, AC. and Evan, GI. (1994b) Inhibition of vascular smooth muscle cell proliferation in vitro and in vivo by c-myc antisense oligodeoxynucleotides. Journal of Clinical Investigation 93:820-8.
Bennett, MR., Littlewood, TD., Hancock, DC., Evan, GI. and Newby, AC. (1994a) Down-regulation of the c-myc proto-oncogene in inhibition of vascular smooth-muscle cell proliferation: a signal for growth arrest? Biochemical Journal 302:701-8.
Brand, K., Page, S., Rogler, G., Bartsch, A., Brandl, R. Knuechel, R., Page, M., Kaltschmidt, C., Baeuerle, PA. and Neumeier, D. (1996) Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. Journal of Clinical Investigation 97:1715-22.
Braun-Dullaeus, RC., Mann, MJ. and Dzau, VJ. (1998) Cell cycle progression: new therapeutic target for vascular proliferative disease. Circulation 98:82-9.
Brennan, P., Babbage, JW., Burgering, BM., Groner, B., Reif, K. and Cantrell, DA. (1997) Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity 7:679-89.
Brinkman, HJ., van Buul-Wortelboer, MF. and van Mourik, JA. (1990) Involvement of cyclooxygenase- and lipoxygenase-mediated conversion of arachidonic acid in controlling human vascular smooth muscle cell proliferation. Thrombosis & Haemostasis 63:291-7.
Brinkman, HJ., van Buul-Wortelboer, MF. and van Mourik, JA. (1991) Selective conversion and esterification of monohydroxy-eicosatetraenoic acids by human vascular smooth muscle cells: relevance to smooth muscle cell proliferation. Experimental Cell Research 192:87-92.
Brown, KE., Kindy, MS. and Sonenshein, GE. (1992) Expression of the c-myb proto-oncogene in bovine vascular smooth muscle cells. Journal of Biological Chemistry 267:4625-30.
Cai, H., Szeberenyi, J. and Cooper, GM. (1990) Effect of a dominant inhibitory Ha-ras mutation on mitogenic signal transduction in NIH 3T3 cells. Molecular & Cellular Biology10:5314-23.
Campan, M., Desgranges, C., Gadeau, AP., Millet, D. and Belloc, F. (1992) Cell cycle dependent gene expression in quiescent stimulated and asynchronously cycling arterial smooth muscle cells in culture. Journal of Cellular Physiology 150:493-500.
Campbell, GR. and Campbell, JH. (1990) The phenotypes of smooth muscle expressed in human atheroma. Annals of the New York Academy of Sciences 598:143-58.
Castellot, JJ Jr., Cochran, DL. and Karnovsky, MJ.(1985) Effect of heparin on vascular smooth muscle cells. I. Cell metabolism. Journal of Cellular Physiology 124:21-8.
Cayatte, AJ., Palacino, JJ., Horten, K. and Cohen, RA. (1994) Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arteriosclerosis & Thrombosis 14:753-9.
Cercek, B., Yamashita, M., Dimayuga, P., Zhu, J., Fishbein, MC., Kaul, S., Shah, PK., Nilsson, J. and Regnstrom, J. (1997) Nuclear factor-kappaB activity and arterial response to balloon injury. Atherosclerosis 131:59-66.
Chen, L., Daum, G., Forough, R., Clowes, M., Walter, U. and Clowes, AW. (1998) Overexpression of human endothelial nitric oxide synthase in rat vascular smooth muscle cells and in balloon-injured carotid artery. Circulation Research 82:862-70.
Cheng, M., Sexl, V., Sherr, CJ. and Roussel, MF. (1998) Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proceedings of the National Academy of Sciences of the United States of America 95:1091-6.
Chomczynski, P. and Sacchi, N. (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analytical Biochemistry 162:156-9.
Clinton, SK., Underwood, R., Hayes, L., Sherman, ML., Kufe, DW. and Libby, P. (1992) Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis. American Journal of Pathology 140:301-16.
Daksis, JI., Lu, RY. Facchini, LM., Marhin, WW. and Penn, LJ. (1994) Myc induces cyclin D1 expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle. Oncogene 9:3635-45.
Diaz-Meco, MT., Municio, MM., Sanchez, P., Lozano, J. and Moscat, J. (1996) Lambda-interacting protein, a novel protein that specifically interacts with the zinc finger domain of the atypical protein kinase C isotype lambda/iota and stimulates its kinase activity in vitro and in vivo. Molecular & Cellular Biology 16:105-14.
Diehl, JA., Cheng, M., Roussel, MF. and Sherr, CJ. (1998) Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes & Development 12:3499-511.
Ding, XZ., Kuszynski, CA., El-Metwally, TH. and Adrian, TE.(1999) Lipoxygenase inhibition induced apoptosis, morphological changes, and carbonic anhydrase expression in human pancreatic cancer cells. Biochemical & Biophysical Research Communications 266:392-9.
Downward, J. (1997) Cell cycle: routine role for Ras. Current Biology 7:R258-60.
Elledge, SJ. (1996) Cell cycle checkpoints: preventing an identity crisis. Science 274:1664-72.
Fafeur, V., Jiang, ZP. and Bohlen, P. (1991) Signal transduction by bFGF, but not TGF beta 1, involves arachidonic acid metabolism in endothelial cells. Journal of Cellular Physiology 149:277-83.
Fujio, Y., Guo, K., Mano, T., Mitsuuchi, Y., Testa, JR. and Walsh, K. (1999) Cell cycle withdrawal promotes myogenic induction of Akt, a positive modulator of myocyte survival. Molecular & Cellular Biology 19:5073-82.
Fukumoto, S., Koyama, H., Hosoi, M., Yamakawa, K., Tanaka, S., Morii, H. and Nishizawa, Y. (1999) Distinct role of cAMP and cGMP in the cell cycle control of vascular smooth muscle cells: cGMP delays cell cycle transition through suppression of cyclin D1 and cyclin-dependent kinase 4 activation. Circulation Research 85:985-91.
Fukumoto, S., Nishizawa, Y., Hosoi, M., Koyama, H., Yamakawa, K., Ohno, S. and Morii, H. (1997) Protein kinase C delta inhibits the proliferation of vascular smooth muscle cells by suppressing G1 cyclin expression. Journal of Biological Chemistry 272:13816-22.
Fuster, V., Badimon, L., Badimon, JJ. and Chesebro, JH. (1992) The pathogenesis of coronary artery disease and the acute coronary syndromes (1). New England Journal of Medicine 326:242-50.
Gao, Z., Huang, K., Yang, X. and Xu, H. (1999) Free radical scavenging and antioxidant activities of flavonoids extracted from the radix of Scutellaria baicalensis Georgi. Biochimica et Biophysica Acta. 1472:643-50.
Garrington, TP. and Johnson, GL. (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways. Current Opinion in Cell Biology 11:211-8.
Ghosh, S., May, MJ. and Kopp, EB. (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annual Review of Immunology 16:225-60.
Gilani, AH., Janbaz, KH. and Shah, BH. (1998) Esculetin prevents liver damage induced by paracetamol and CCL4. Pharmacological Research 37:31-5.
Gille, H. and Downward, J. (1999) Multiple ras effector pathways contribute to G(1) cell cycle progression. Journal of Biological Chemistry 274:22033-40.
Gorski, DH. and Walsh, K. (1995) Mitogen-responsive nuclear factors that mediate growth control signals in vascular myocytes. Cardiovascular Research 30:585-92.
Green, LC., Wagner, DA., Glogowski, J., Skipper, PL., Wishnok, JS. and Tannenbaum, SR. (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Analytical Biochemistry 126(1):131-8.
Grilli, M., Chiu, JJ. and Lenardo, MJ. (1993) NF-kappa B and Rel: participants in a multiform transcriptional regulatory system. International Review of Cytology 143:1-62.
Gruber, JR., Ohno, S. and Niles, RM. (1992) Increased expression of protein kinase C alpha plays a key role in retinoic acid-induced melanoma differentiation. Journal of Biological Chemistry 267:13356-60.
Guo, K., Andres, V. and Walsh, K. (1998) Nitric oxide-induced downregulation of Cdk2 activity and cyclin A gene transcription in vascular smooth muscle cells. Circulation 97:2066-72.
Han, EK., Cacace, AM., Sgambato, A. and Weinstein, IB. (1995) Altered expression of cyclins and c-fos in R6 cells that overproduce PKC epsilon. Carcinogenesis 16:2423-8.
Hanahan, DJ. (1986) Platelet activating factor: a biologically active phosphoglyceride. Annual Review of Biochemistry 55:483-509.
Hanasaki, Y., Ogawa, S. and Fukui, S. (1994) The correlation between active oxygens scavenging and antioxidative effects of flavonoids. Free Radical Biology & Medicine 16:845-50.
Handler, JA., Danilowicz, RM. and Eling, TE. (1990) Mitogenic signaling by epidermal growth factor (EGF), but not platelet-derived growth factor, requires arachidonic acid metabolism in BALB/c 3T3 cells. Modulation of EGF-dependent c-myc expression by prostaglandins. Journal of Biological Chemistry 265:3669-73.
Harris, RC., Homma, T., Jacobson, HR. and Capdevila, J. (1990) Epoxyeicosatrienoic acids activate Na+/H+ exchange and are mitogenic in cultured rat glomerular mesangial cells. Journal of Cellular Physiology 144:429-37.
Havsteen, B. (1983) Flavonoids, a class of natural products of high pharmacological potency. Biochemical Pharmacology 32:1141-8.
Hedin, U. and Thyberg, J. (1987) Plasma fibronectin promotes modulation of arterial smooth-muscle cells from contractile to synthetic phenotype. Differentiation 33:239-46.
Hirai, S., Izumi, Y., Higa, K., Kaibuchi, K., Mizuno, K., Osada, S., Suzuki, K. and Ohno, S. (1994) Ras-dependent signal transduction is indispensable but not sufficient for the activation of AP1/Jun by PKC delta. EMBO Journal 13:2331-40.
Hiscott, J., Marois, J., Garoufalis, J., D'Addario, M., Roulston, A., Kwan, I., Pepin, N., Lacoste, J., Nguyen, H., Bensi, G., et al. (1993) Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop. Molecular & Cellular Biology 13:6231-40.
Hishikawa, K., Oemar, BS., Yang, Z. and Luscher, TF. (1997) Pulsatile stretch stimulates superoxide production and activates nuclear factor-kappa B in human coronary smooth muscle. Circulation Research 81:797-803.
Hofmanova, J., Musilova, E. and Kozubik, A. (1996) Suppression of human cancer cell proliferation by lipoxygenase inhibitors and gamma-radiation in vitro. General Physiology & Biophysics 15:317-31.
Hoshi, S., Goto, M., Koyama, N., Nomoto, K. and Tanaka, H. (2000) Regulation of vascular smooth muscle cell proliferation by nuclear factor-kappaB and its inhibitor, I-kappaB. Journal of Biological Chemistry 275:883-9.
Huang, HC., Hsieh, LM., Chen, HW., Lin, YS. and Chen, JS. (1994) Effects of baicalein and esculetin on transduction signals and growth factors expression in T-lymphoid leukemia cells. European Journal of Pharmacology 268:73-8.
Huang, HC., Lai, MW., Wang, HR., Chung, YL., Hsieh, LM. and Chen, CC. (1993) Antiproliferative effect of esculetin on vascular smooth muscle cells: possible roles of signal transduction pathways. European Journal of Pharmacology 237:39-44.
Hunter, T. (1997) Oncoprotein networks. Cell 88:333-46.
Ikemoto, S., Sugimura, K., Yoshida, N., Yasumoto, R., Wada, S., Yamamoto, K. and Kishimoto, T. (2000) Antitumor effects of Scutellariae radix and its components baicalein, baicalin, and wogonin on bladder cancer cell lines. Urology 55:951-5.
Indolfi, C., Avvedimento, EV., Di Lorenzo, E., Esposito, G., Rapacciuolo, A., Giuliano, P., Grieco, D., Cavuto, L., Stingone, AM., Ciullo, I., Condorelli, G. and Chiariello, M. (1997) Activation of cAMP-PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury. Nature Medicine 3:775-9.
Indolfi, C., Avvedimento, EV., Rapacciuolo, A., Di Lorenzo, E., Esposito, G., Stabile, E., Feliciello, A., Mele, E., Giuliano, P., Condorelli, G., et al. (1995) Inhibition of cellular ras prevents smooth muscle cell proliferation after vascular injury in vivo. Nature Medicine 1:541-5.
Inoue, T. and Jackson, EK. (1999) Strong antiproliferative effects of baicalein in cultured rat hepatic stellate cells. European Journal of Pharmacology 378:129-35.
Irvine, RF. (1982) How is the level of free arachidonic acid controlled in mammalian cells?. Biochemical Journal 204:3-16.
Ishida, A., Sasaguri, T., Kosaka, C., Nojima, H. and Ogata J. (1997) Induction of the cyclin-dependent kinase inhibitor p21(Sdi1 /Cip1/Waf1) by nitric oxide-generating vasodilator in vascular smooth muscle cells. Journal of Biological Chemistry 272:10050-7.
Kimura, Y., Okuda, H. and Arichi, S. (1987) Effects of baicalein on leukotriene biosynthesis and degranulation in human polymorphonuclear leukocytes. Biochimica et Biophysica Acta. 922:278-86.
Kimura, Y., Okuda, H., Arichi, S., Baba, K. and Kozawa, M. (1985) Inhibition of the formation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid from arachidonic acid in polymorphonuclear leukocytes by various coumarins. Biochimica et Biophysica Acta. 834(2):224-9.
Kindy, MS. and Sonenshein, GE. (1986) Regulation of oncogene expression in cultured aortic smooth muscle cells. Post-transcriptional control of c-myc mRNA. Journal of Biological Chemistry 261:12865-8.
Landry, DB., Couper, LL., Bryant, SR. and Lindner, V. (1997) Activation of the NF-kappa B and I kappa B system in smooth muscle cells after rat arterial injury. Induction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. American Journal of Pathology 151:1085-95.
Lavoie, JN., L'Allemain, G., Brunet, A., Muller, R. and Pouyssegur, J. (1996) Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. Journal of Biological Chemistry 271:20608-16.
Lee, MW. and Severson, DL. (1994) Signal transduction in vascular smooth muscle: diacylglycerol second messengers and PKC action. American Journal of Physiology 267:C659-78.
Leone, G., DeGregori, J., Sears, R., Jakoi, L. and Nevins, JR. (1997) Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F [published erratum appears in Nature 1997 Jun 26;387(6636):932]. Nature 387:422-6.
Libby, P. and Tanaka, H. (1997) The molecular bases of restenosis. Progress in Cardiovascular Diseases 40:97-106.
Libby, P., Friedman, GB. and Salomon, RN. (1989) Cytokines as modulators of cell proliferation in fibrotic diseases. American Review of Respiratory Disease 140:1114-7.
Libby, P., Schwartz, D., Brogi, E., Tanaka, H. and Clinton, SK. (1992) A cascade model for restenosis. A special case of atherosclerosis progression. Circulation 86:III47-52.
Livneh, E. and Fishman, DD. (1997) Linking protein kinase C to cell-cycle control. European Journal of Biochemistry 248:1-9.
Lundergan, CF., Foegh, ML. and Ramwell, PW. (1991) Peptide inhibition of myointimal proliferation by angiopeptin, a somatostatin analogue. Journal of the American College of Cardiology 17:132B-136B.
Majack, RA. (1987) Beta-type transforming growth factor specifies organizational behavior in vascular smooth muscle cell cultures. Journal of Cell Biology 105:465-71.
Majesky, MW., Benditt, EP. and Schwartz, SM. (1988) Expression and developmental control of platelet-derived growth factor A-chain and B-chain/Sis genes in rat aortic smooth muscle cells. Proceedings of the National Academy of Sciences of the United States of America 85:1524-8.
Majesky, MW., Daemen, MJ. and Schwartz, SM. (1990) Alpha 1-adrenergic stimulation of platelet-derived growth factor A-chain gene expression in rat aorta. Journal of Biological Chemistry 265:1082-8.
Marshall, CJ. (1996) Ras effectors. Current Opinion in Cell Biology 8:197-204.
Matsuo, H., Li, H., McGuire, AM., Fletcher, CM., Gingras, AC., Sonenberg, N. and Wagner, G. (1997) Structure of translation factor eIF4E bound to m7GDP and interaction with 4E-binding protein. Nature Structural Biology 4:717-24.
Miano, JM., Tota, RR., Vlasic, N. Danishefsky, KJ. and Stemerman, MB. (1990) Early proto-oncogene expression in rat aortic smooth muscle cells following endothelial removal. American Journal of Pathology 137:761-5.
Miano, JM., Vlasic, N., Tota, RR. and Stemerman, MB. (1993) Localization of Fos and Jun proteins in rat aortic smooth muscle cells after vascular injury. American Journal of Pathology 142:715-24.
Middleton, E Jr. and Kandaswami, C. (1992) Effects of flavonoids on immune and inflammatory cell functions. Biochemical Pharmacology 43:1167-79.
Moncada, S., Palmer, RM. and Higgs, EA. (1990) Relationship between prostacyclin and nitric oxide in the thrombotic process. Thrombosis Research - Supplement 11:3-13.
Moncada, S., Palmer, RM. and Higgs, EA. (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacological Reviews 43:109-42.
Morisaki, N., Kanzaki, T., Motoyama, N., Saito, Y. and Yoshida, S. (1988) Cell cycle-dependent inhibition of DNA synthesis by prostaglandin I2 in cultured rabbit aortic smooth muscle cells. Atherosclerosis 71:165-71.
Muller, DW. (1997) The role of proto-oncogenes in coronary restenosis. Progress in Cardiovascular Diseases 40:117-28.
Nabel, EG., Yang, ZY., Plautz, G., Forough, R., Zhan, X., Haudenschild, CC., Maciag, T. and Nabel, GJ. (1993) Recombinant fibroblast growth factor-1 promotes intimal hyperplasia and angiogenesis in arteries in vivo. Nature 362:844-6.
Nava, E., Noll, G. and Luscher, TF. (1995) Nitric oxide in cardiovascular diseases. Annals of Medicine 27:343-51.
Nilsson, J., Sjolund, M., Palmberg, L., Thyberg, J. and Heldin, CH. (1985) Arterial smooth muscle cells in primary culture produce a platelet-derived growth factor-like protein. Proceedings of the National Academy of Sciences of the United States of America 82:4418-22.
Nishizuka, Y. (1995) Protein kinase C and lipid signaling for sustained cellular responses. FASEB Journal 9:484-96.
Ono, K., Nakane, H., Fukushima, M., Chermann, JC. and Barre-Sinoussi, F. (1989) Inhibition of reverse transcriptase activity by a flavonoid compound, 5,6,7-trihydroxyflavone. Biochemical & Biophysical Research Communications 160:982-7.
Owen, NE. (1986) Effect of prostaglandin E1 on DNA synthesis in vascular smooth muscle cells. American Journal of Physiology 250:C584-8.
Palmberg, L., Claesson, HE. and Thyberg, J. (1987) Leukotrienes stimulate initiation of DNA synthesis in cultured arterial smooth muscle cells. Journal of Cell Science 88:151-9.
Pardee, AB. (1989) G1 events and regulation of cell proliferation. Science 246:603-8.
Parkes, JL., Cardell, RR., Hubbard, FC Jr., Hubbard, D., Meltzer, A. and Penn, A. (1991) Cultured human atherosclerotic plaque smooth muscle cells retain transforming potential and display enhanced expression of the myc protooncogene. American Journal of Pathology 138:765-75.
Paya, M., Halliwell, B. and Hoult, JR. (1992) Interactions of a series of coumarins with reactive oxygen species. Scavenging of superoxide, hypochlorous acid and hydroxyl radicals. Biochemical Pharmacology 44:205-14.
Phuchareon, J. and Tokuhisa, T. (1995) Deregulated c-Fos/AP-1 modulates expression of the cyclin and the cdk gene in splenic B cells stimulated with lipopolysaccharide. Cancer Letters 92:203-8.
Pukac, LA., Castellot, JJ Jr., Wright, TC Jr., Caleb, BL. and Karnovsky, MJ. (1990) Heparin inhibits c-fos and c-myc mRNA expression in vascular smooth muscle cells. Cell Regulation 1:435-43.
Rao, GN. and Berk, BC. (1992) Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression. Circulation Research 70:593-9.
Reilly, CF., Kindy, MS., Brown, KE., Rosenberg, RD. and Sonenshein, GE. (1989) Heparin prevents vascular smooth muscle cell progression through the G1 phase of the cell cycle. Journal of Biological Chemistry 264:6990-5.
Rivard, A. and Andres, V. (2000) Vascular smooth muscle cell proliferation in the pathogenesis of atherosclerotic cardiovascular diseases. Histology & Histopathology 15:557-71.
Rodes, J., Cote, G., Lesperance, J., Bourassa, MG., Doucet, S., Bilodeau, L., Bertrand, OF., Harel, F., Gallo, R.and Tardif,JC. (1998) Prevention of restenosis after angioplasty in small coronary arteries with probucol. Circulation 97:429-36.
Ross, R. (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801-9.
Ross, R. and Glomset, JA. (1976) The pathogenesis of atherosclerosis (first of two parts). New England Journal of Medicine 295:369-77.
Rothman, A., Wolner, B., Button, D. and Taylor, P. (1994) Immediate-early gene expression in response to hypertrophic and proliferative stimuli in pulmonary arterial smooth muscle cells. Journal of Biological Chemistry 269:6399-404.
Salhany, KE., Robinson-Benion, C., Candia, AF., Pledger, WJ. and Holt, JT. (1992) Differential induction of the c-fos promoter through distinct PDGF receptor-mediated signaling pathways. Journal of Cellular Physiology 150:386-95.
Schramek, H., Feifel, E., Healy, E. and Pollack, V. (1997) Constitutively active mutant of the mitogen-activated protein kinase kinase MEK1 induces epithelial dedifferentiation and growth inhibition in madin-darby canine kidney-C7 cells. Journal of Biological Chemistry 272:11426-33.
Schwartz, RS., Holmes, DR Jr. and Topol, EJ. (1992) The restenosis paradigm revisited: an alternative proposal for cellular mechanisms. Journal of the American College of Cardiology 20:1284-93.
Sekiya, K. and Okuda, H. (1982) Selective inhibition of platelet lipoxygenase by baicalein. Biochemical & Biophysical Research Communications 105:1090-5.
Sellmayer, A., Uedelhoven, WM., Weber, PC. and Bonventre, JV. (1991) Endogenous non-cyclooxygenase metabolites of arachidonic acid modulate growth and mRNA levels of immediate-early response genes in rat mesangial cells. Journal of Biological Chemistry 266:3800-7.
Setty, BN., Graeber, JE. and Stuart, MJ. (1987) The mitogenic effect of 15- and 12-hydroxyeicosatetraenoic acid on endothelial cells may be mediated via diacylglycerol kinase inhibition. Journal of Biological Chemistry 262:17613-22.
Shanahan, CM. and Weissberg, PL. (1999) Smooth muscle cell phenotypes in atherosclerotic lesions. Current Opinion in Lipidology 10:507-13.
Shao, ZH., Li, CQ., Vanden Hoek, TL., Becker, LB., Schumacker, PT., Wu, JA., Attele, AS. and Yuan, CS. (1999) Extract from Scutellaria baicalensis Georgi attenuates oxidant stress in cardiomyocytes. Journal of Molecular & Cellular Cardiology 31:1885-95.
Shichiri, M., Hanson, KD. and Sedivy, JM. (1993) Effects of c-myc expression on proliferation, quiescence, and the G0 to G1 transition in nontransformed cells. Cell Growth & Differentiation 4:93-104.
Siegel, MI., McConnell, RT., Bonser, RW. and Cuatrecasas, P. (1982) The lipoxygenase product, 5-hydroperoxy-arachidonic acid, augments chemotactic peptide-stimulated arachidonic acid release from HL60 granulocytes. Biochemical & Biophysical Research Communications 104:874-81.
Sjolund, M., Rahm, M., Claesson-Welsh, L., Sejersen, T., Heldin, CH. and Thyberg, J. (1990) Expression of PDGF alpha- and beta-receptors in rat arterial smooth muscle cells is phenotype and growth state dependent. Growth Factors 3:191-203.
Steiner, P., Philipp, A., Lukas J., Godden-Kent, D., Pagano, M., Mittnacht S., Bartek J. and Eilers M. (1995) Identification of a Myc-dependent step during the formation of active G1 cyclin-cdk complexes. EMBO Journal 14:4814-26.
Strauss, BH., Chisholm, RJ., Keeley, FW., Gotlieb, AI., Logan, RA. and Armstrong, PW. (1994) Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis. Circulation Research 75:650-8.
Sylvester, AM., Chen, D., Krasinski, K.and Andres, V. (1998) Role of c-fos and E2F in the induction of cyclin A transcription and vascular smooth muscle cell proliferation. Journal of Clinical Investigation 101:940-8.
Takahashi, E. and Berk, BC. (1998) MAP kinases and vascular smooth muscle function. Acta Physiologica Scandinavica 164:611-21.
Tardif, JC., Cote, G., Lesperance, J., Bourassa, M., Lambert, J., Doucet, S., Bilodeau, L., Nattel, S. and de Guise, P. (1997) Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. New England Journal of Medicine 337:365-72.
Taubman, MB., Berk, BC., Izumo, S., Tsuda, T., Alexander, RW.,and Nadal-Ginard, B. (1989) Angiotensin II induces c-fos mRNA in aortic smooth muscle. Role of Ca2+ mobilization and protein kinase C activation. Journal of Biological Chemistry 264:526-30.
Thyberg, J. (1998) Phenotypic modulation of smooth muscle cells during formation of neointimal thickenings following vascular injury. Histology & Histopathology 13:871-91.
Thyberg, J., Hedin, U., Sjolund, M., Palmberg, L. and Bottger, BA. (1990) Regulation of differentiated properties and proliferation of arterial smooth muscle cells. Arteriosclerosis 10:966-90.
Topol, EJ., Califf, RM., Weisman, HF., Ellis, SG., Tcheng, JE., Worley, S., Ivanhoe, R., George, BS., Fintel, D., Weston, M. et al. (1994) Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 343:881-6.
Tsai, JC., Jain, M., Hsieh, CM., Lee, WS., Yoshizumi, M., Patterson, C., Perrella, MA., Cooke, C., Wang, H., Haber, E., Schlegel, R. and Lee, ME. (1996) Induction of apoptosis by pyrrolidinedithiocarbamate and N-acetylcysteine in vascular smooth muscle cells. Journal of Biological Chemistry 271:3667-70.
Ueno, H., Yamamoto, H., Ito, S., Li, JJ. and Takeshita, A. (1997) Adenovirus-mediated transfer of a dominant-negative H-ras suppresses neointimal formation in balloon-injured arteries in vivo. Arteriosclerosis, Thrombosis & Vascular Biology 17:898-904.
Vadiveloo, PK., Filonzi, EL., Stanton, HR. and Hamilton, JA. (1997) G1 phase arrest of human smooth muscle cells by heparin, IL-4 and cAMP is linked to repression of cyclin D1 and cdk2. Atherosclerosis 133:61-9.
Weber, JD., Raben, DM., Phillips, PJ. and Baldassare, JJ. (1997) Sustained activation of extracellular-signal-regulated kinase 1 (ERK1) is required for the continued expression of cyclin D1 in G1 phase. Biochemical Journal 326:61-8.
Whalen, AM., Galasinski, SC., Shapiro, PS., Nahreini, TS. and Ahn, NG. (1997) Megakaryocytic differentiation induced by constitutive activation of mitogen-activated protein kinase kinase. Molecular & Cellular Biology 17:1947-58.
Woods, D., Parry, D., Cherwinski, H., Bosch, E., Lees, E. and McMahon, M. (1997) Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Molecular & Cellular Biology 17:5598-611.
Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., Yazaki, Y., Goto, K. and Masaki, T. (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411-5.
Yano, H., Mizoguchi, A., Fukuda, K., Haramaki, M., Ogasawara, S., Momosaki, S. and Kojiro, M. (1994) The herbal medicine sho-saiko-to inhibits proliferation of cancer cell lines by inducing apoptosis and arrest at the G0/G1 phase. Cancer Research 54:448-54.
Yokoi, H., Daida, H., Kuwabara, Y., Nishikawa, H., Takatsu, F., Tomihara, H., Nakata, Y., Kutsumi, Y., Ohshima, S., Nishiyama, S., Seki, A., Kato, K., Nishimura, S., Kanoh, T. and Yamaguchi, H. (1997) Effectiveness of an antioxidant in preventing restenosis after percutaneous transluminal coronary angioplasty: the Probucol Angioplasty Restenosis Trial. Journal of the American College of Cardiology 30:855-62.
Yu, SM., Hung, LM. and Lin, CC. (1997) cGMP-elevating agents suppress proliferation of vascular smooth muscle cells by inhibiting the activation of epidermal growth factor signaling pathway. Circulation 95:1269-77.