Pigment epithelium-derived factor reduces the PDGF-induced migration and proliferation of human aortic smooth muscle cells through PPARγ activation

Shu-Huei Wang, Chan-Jung Liang, Jiahn-Chun Wu, Jiuan-Jiuan Huang, Hsiung-Fei Chien, Jaw-Shiun Tsai, Yuh-Siu Yen, Ying-Chih Tseng, June-Horng Lue, Yuh-Lien Chen

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Our previous study demonstrated that pigment epithelium-derived factor (PEDF) plays an important role in the proliferation and migration of human aortic smooth muscle cells (HASMCs). In the present study, we examined whether PEDF inhibited platelet-derived growth factor (PDGF)-stimulated HASMC migration and proliferation. PEDF dose-dependently reduced PDGF-induced HASMC migration and proliferation in vitro and also arrested cell cycle progression in the G0/G1 phase, and this was associated with decreased expression of cyclin D1, cyclin E, CDK2, CDK4, and p21 Cip1 and increased expression of the cyclin-dependent kinase inhibitor p27 Kip1. The antiproliferative and antimigratory effects of PEDF were partially blocked by the PPARγ antagonist GW9662, but not by the PPARα antagonist MK886. In in vivo studies, the femoral artery of C57BL/6 mice was endothelial-denuded and the mice injected intravenously with PEDF or vehicle. After 2 weeks, both the neointima/media area ratio and cell proliferation (proliferating cell nuclear antigen-positive cells) in the neointima were significantly reduced and again these effects were partially reversed by GW9662 pretreatment. Our data show that PEDF increases PPARγ activation, preventing entry of HASMCs into the cell cycle in vitro and reducing the neointimal area and cell proliferation in the neointima in vivo. Thus, PEDF may represent a safe and effective novel target for the prevention and treatment of vascular proliferative diseases. © 2011 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)280-289
Number of pages10
JournalInternational Journal of Biochemistry and Cell Biology
Volume44
Issue number2
DOIs
Publication statusPublished - 2012
Externally publishedYes

Fingerprint

Peroxisome Proliferator-Activated Receptors
Platelet-Derived Growth Factor
Smooth Muscle Myocytes
Muscle
Chemical activation
Cells
Neointima
Cell Proliferation
Cell proliferation
Cell Movement
Cell Cycle
Cyclin-Dependent Kinase Inhibitor p27
Cyclin E
Cell Cycle Resting Phase
Cyclin D1
Proliferating Cell Nuclear Antigen
G1 Phase
Femoral Artery
pigment epithelium-derived factor
Inbred C57BL Mouse

Keywords

  • Cell cycle
  • Neointimal hyperplasia
  • PEDF
  • PPARγ
  • Proliferation
  • 2 chloro 5 nitrobenzanilide
  • cyclin D1
  • cyclin dependent kinase 2
  • cyclin dependent kinase 4
  • cyclin dependent kinase inhibitor 1
  • cyclin dependent kinase inhibitor 1B
  • cyclin E
  • cycline
  • peroxisome proliferator activated receptor gamma
  • pigment epithelium derived factor
  • platelet derived growth factor
  • animal experiment
  • animal model
  • animal tissue
  • antiproliferative activity
  • aorta media
  • artery intima proliferation
  • article
  • blood vessel injury
  • cell cycle G0 phase
  • cell cycle progression
  • cell migration
  • cell proliferation
  • concentration response
  • controlled study
  • femoral artery
  • G1 phase cell cycle checkpoint
  • human
  • human cell
  • male
  • mouse
  • neointima
  • nonhuman
  • protein expression
  • smooth muscle fiber
  • Western blotting
  • Animals
  • Aorta
  • Cell Cycle
  • Cell Movement
  • Cell Proliferation
  • Eye Proteins
  • Humans
  • Mice
  • Muscle, Smooth, Vascular
  • Neointima
  • Nerve Growth Factors
  • Platelet-Derived Growth Factor
  • PPAR gamma
  • Serpins
  • Mus

Cite this

Pigment epithelium-derived factor reduces the PDGF-induced migration and proliferation of human aortic smooth muscle cells through PPARγ activation. / Wang, Shu-Huei; Liang, Chan-Jung; Wu, Jiahn-Chun; Huang, Jiuan-Jiuan; Chien, Hsiung-Fei; Tsai, Jaw-Shiun; Yen, Yuh-Siu; Tseng, Ying-Chih; Lue, June-Horng; Chen, Yuh-Lien.

In: International Journal of Biochemistry and Cell Biology, Vol. 44, No. 2, 2012, p. 280-289.

Research output: Contribution to journalArticle

Wang, Shu-Huei ; Liang, Chan-Jung ; Wu, Jiahn-Chun ; Huang, Jiuan-Jiuan ; Chien, Hsiung-Fei ; Tsai, Jaw-Shiun ; Yen, Yuh-Siu ; Tseng, Ying-Chih ; Lue, June-Horng ; Chen, Yuh-Lien. / Pigment epithelium-derived factor reduces the PDGF-induced migration and proliferation of human aortic smooth muscle cells through PPARγ activation. In: International Journal of Biochemistry and Cell Biology. 2012 ; Vol. 44, No. 2. pp. 280-289.
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title = "Pigment epithelium-derived factor reduces the PDGF-induced migration and proliferation of human aortic smooth muscle cells through PPARγ activation",
abstract = "Our previous study demonstrated that pigment epithelium-derived factor (PEDF) plays an important role in the proliferation and migration of human aortic smooth muscle cells (HASMCs). In the present study, we examined whether PEDF inhibited platelet-derived growth factor (PDGF)-stimulated HASMC migration and proliferation. PEDF dose-dependently reduced PDGF-induced HASMC migration and proliferation in vitro and also arrested cell cycle progression in the G0/G1 phase, and this was associated with decreased expression of cyclin D1, cyclin E, CDK2, CDK4, and p21 Cip1 and increased expression of the cyclin-dependent kinase inhibitor p27 Kip1. The antiproliferative and antimigratory effects of PEDF were partially blocked by the PPARγ antagonist GW9662, but not by the PPARα antagonist MK886. In in vivo studies, the femoral artery of C57BL/6 mice was endothelial-denuded and the mice injected intravenously with PEDF or vehicle. After 2 weeks, both the neointima/media area ratio and cell proliferation (proliferating cell nuclear antigen-positive cells) in the neointima were significantly reduced and again these effects were partially reversed by GW9662 pretreatment. Our data show that PEDF increases PPARγ activation, preventing entry of HASMCs into the cell cycle in vitro and reducing the neointimal area and cell proliferation in the neointima in vivo. Thus, PEDF may represent a safe and effective novel target for the prevention and treatment of vascular proliferative diseases. {\circledC} 2011 Elsevier Ltd. All rights reserved.",
keywords = "Cell cycle, Neointimal hyperplasia, PEDF, PPARγ, Proliferation, 2 chloro 5 nitrobenzanilide, cyclin D1, cyclin dependent kinase 2, cyclin dependent kinase 4, cyclin dependent kinase inhibitor 1, cyclin dependent kinase inhibitor 1B, cyclin E, cycline, peroxisome proliferator activated receptor gamma, pigment epithelium derived factor, platelet derived growth factor, animal experiment, animal model, animal tissue, antiproliferative activity, aorta media, artery intima proliferation, article, blood vessel injury, cell cycle G0 phase, cell cycle progression, cell migration, cell proliferation, concentration response, controlled study, femoral artery, G1 phase cell cycle checkpoint, human, human cell, male, mouse, neointima, nonhuman, protein expression, smooth muscle fiber, Western blotting, Animals, Aorta, Cell Cycle, Cell Movement, Cell Proliferation, Eye Proteins, Humans, Mice, Muscle, Smooth, Vascular, Neointima, Nerve Growth Factors, Platelet-Derived Growth Factor, PPAR gamma, Serpins, Mus",
author = "Shu-Huei Wang and Chan-Jung Liang and Jiahn-Chun Wu and Jiuan-Jiuan Huang and Hsiung-Fei Chien and Jaw-Shiun Tsai and Yuh-Siu Yen and Ying-Chih Tseng and June-Horng Lue and Yuh-Lien Chen",
note = "被引用次數:6 Export Date: 16 March 2016 CODEN: IJBBF 通訊地址: Lue, J.-H.; Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan; 電子郵件: thomas@ntu.edu.tw 化學物質/CAS: cyclin dependent kinase 2, 141349-86-2; cyclin dependent kinase 4, 147014-97-9; pigment epithelium derived factor, 197980-93-1; Eye Proteins; Nerve Growth Factors; PPAR gamma; Platelet-Derived Growth Factor; Serpins; pigment epithelium-derived factor 參考文獻: Abe, R., Fujita, Y., Yamagishi, S., Shimizu, H., Pigment epithelium-derived factor prevents melanoma growth via angiogenesis inhibition (2008) Curr Pharm des, 14, pp. 3802-3809; Andres, V., Castro, C., Antiproliferative strategies for the treatment of vascular proliferative disease (2003) Curr Vasc Pharmacol, 1, pp. 85-98; Bardot, O., Aldridge, T.C., Latruffe, N., Green, S., PPAR-RXR heterodimer activates a peroxisome proliferator response element upstream of the bifunctional enzyme gene (1993) Biochemical and Biophysical Research Communications, 192 (1), pp. 37-45. , DOI 10.1006/bbrc.1993.1378; Benson, S., Wu, J., Padmanabhan, S., Kurtz, T.W., Pershadsingh, H.A., Peroxisome proliferator-activated receptor (PPAR)-γ expression in human vascular smooth muscle cells: Inhibition of growth, migration, and c-fos expression by the peroxisome proliferator-activated receptor (PPAR)-γ activator troglitazone (2000) American Journal of Hypertension, 13 (1), pp. 74-82. , DOI 10.1016/S0895-7061(99)00148-X, PII S089570619900148X; Bishop-Bailey, D., Hla, T., Endothelial cell apoptosis induced by the peroxisome proliferator- activated receptor (PPAR) ligand 15-deoxy-Delta12, 14-prostaglandin J2 (1999) J Biol Chem, 274, pp. 17042-17048; Broadhead, M.L., Dass, C.R., Choong, P.F., Systemically administered PEDF against primary and secondary tumours in a clinically relevant osteosarcoma model (2011) Br J Cancer, pp. 1-9; Charron, T., Nili, N., Strauss, B.H., The cell cycle: A critical therapeutic target to prevent vascular proliferative disease (2006) Canadian Journal of Cardiology, 22 (SUPPL. B), pp. 41B-55B; Collino, M., Patel, N.S.A., Lawrence, K.M., Collin, M., Latchman, D.S., Yaqoob, M.M., Thiemermann, C., The selective PPARγ antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion (2005) Kidney International, 68 (2), pp. 529-536. , DOI 10.1111/j.1523-1755.2005.00430.x, PII 4494622; Dawson, D.W., Volpert, O.V., Gillis, P., Crawford, S.E., Xu, H.-J., Benedict, W., Bouck, N.P., Pigment epithelium-derived factor: A potent inhibitor of angiogenesis (1999) Science, 285 (5425), pp. 245-248. , DOI 10.1126/science.285.5425.245; Ek, E.T.H., Dass, C.R., Choong, P.F.M., Pigment epithelium-derived factor: A multimodal tumor inhibitor (2006) Molecular Cancer Therapeutics, 5 (7), pp. 1641-1646. , DOI 10.1158/1535-7163.MCT-06-0107; Ferns, G.A.A., Raines, E.W., Sprugel, K.H., Motani, A.S., Reidy, M.A., Ross, R., Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF (1991) Science, 253 (5024), pp. 1129-1132; Fujimura, T., Yamagishi, S., Ueda, S., Fukami, K., Shibata, R., Matsumoto, Y., Administration of pigment epithelium-derived factor (PEDF) reduces proteinuria by suppressing decreased nephrin and increased VEGF expression in the glomeruli of adriamycin-injected rats (2009) Nephrol Dial Transplant, 24, pp. 1397-1406; Ghosh, S.S., Gehr, T.W.B., Ghosh, S., Fakhry, I., Sica, D.A., Lyall, V., Schoolwerth, A.C., PPARγ ligand attenuates PDGF-induced mesangial cell proliferation: Role of MAP kinase (2003) Kidney International, 64 (1), pp. 52-62. , DOI 10.1046/j.1523-1755.2003.00054.x; Goetze, S., Xi, X.-P., Kawano, H., Gotlibowski, T., Fleck, E., Hsueh, W.A., Law, R.E., PPARγ-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells (1999) Journal of Cardiovascular Pharmacology, 33 (5), pp. 798-806. , DOI 10.1097/00005344-199905000-00018; Hamblin, M., Chang, L., Fan, Y., Zhang, J., Chen, Y.E., PPARs and the cardiovascular system (2009) Antioxid Redox Signal, 11, pp. 1415-1452; Hirsch, J., Johnson, C.L., Nelius, T., Kennedy, R., Riese, W., Filleur, S., PEDF inhibits IL8 production in prostate cancer cells through PEDF receptor/phospholipase A2 and regulation of NF κb and PPARγ (2011) Cytokine, 55, pp. 202-210; Hoshina, D., Abe, R., Yamagishi, S.I., Shimizu, H., The role of PEDF in tumor growth and metastasis (2010) Curr Mol Med, 10, pp. 292-295; Ho, T.C., Chen, S.L., Yang, Y.C., Liao, C.L., Cheng, H.C., Tsao, Y.P., PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells (2007) Cardiovasc Res, 76, pp. 213-223; Ho, T.C., Yang, Y.C., Chen, S.L., Kuo, P.C., Sytwu, H.K., Cheng, H.C., Pigment epithelium-derived factor induces THP-1 macrophage apoptosis and necrosis by the induction of the peroxisome proliferator-activated receptor gamma (2008) Mol Immunol, 45, pp. 898-909; Jiang, H.Y., Petrovas, C., Sonenshein, G.E., Relb-p50 NF-κB complexes are selectively induced by cytomegalovirus immediate-early protein 1: Differential regulation of Bcl-x L promoter activity by NF-κB family members (2002) Journal of Virology, 76 (11), pp. 5737-5747. , DOI 10.1128/JVI.76.11.5737-5747.2002; Law, R.E., Goetze, S., Xi, X.-P., Jackson, S., Kawano, Y., Demer, L., Fishbein, M.C., Hsueh, W.A., Expression and function of PPARγ in rat and human vascular smooth muscle cells (2000) Circulation, 101 (11), pp. 1311-1318; Law, R.E., Meehan, W.P., Xi, X.-P., Graf, K., Wuthrich, D.A., Coats, W., Faxon, D., Hsueh, W.A., Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia (1996) Journal of Clinical Investigation, 98 (8), pp. 1897-1905; Marx, N., Schonbeck, U., Lazar, M.A., Libby, P., Plutzky, J., Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells (1998) Circulation Research, 83 (11), pp. 1097-1103; Nakamura, K., Yamagishi, S.-I., Matsui, T., Yoshida, T., Takenaka, K., Jinnouchi, Y., Yoshida, Y., Imaizumi, T., Pigment epithelium-derived factor inhibits neointimal hyperplasia after vascular injury by blocking NADPH oxidase-mediated reactive oxygen species generation (2007) American Journal of Pathology, 170 (6), pp. 2159-2170. , DOI 10.2353/ajpath.2007.060838; Notari, L., Baladron, V., Aroca-Aguilar, J.D., Balko, N., Heredia, R., Meyer, C., Notario, P.M., Becerra, S.P., Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor (2006) Journal of Biological Chemistry, 281 (49), pp. 38022-38037. , http://www.jbc.org/cgi/reprint/281/49/38022, DOI 10.1074/jbc.M600353200; Ross, R., The pathogenesis of atherosclerosis: A perspective for the 1990 (1993) Nature, 362, pp. 801-809; Sata, M., Maejima, Y., Adachi, F., Fukino, K., Saiura, A., Sugiura, S., A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia (2000) J Mol Cell Cardiol, 32, pp. 2097-2104; Takenaka, K., Yamagishi, S.-i., Matsui, T., Nakamura, K., Jinnouchi, Y., Yoshida, Y., Ueda, S.-i., Imaizumi, T., Pigment epithelium-derived factor (PEDF) administration inhibits occlusive thrombus formation in rats: A possible participation of reduced intraplatelet PEDF in thrombosis of acute coronary syndromes (2008) Atherosclerosis, 197 (1), pp. 25-33. , DOI 10.1016/j.atherosclerosis.2007.07.041, PII S002191500700473X; Tan, M.L., Choong, P.F., Dass, C.R., Anti-chondrosarcoma effects of PEDF mediated via molecules important to apoptosis, cell cycling, adhesion and invasion (2010) Biochem Biophys Res Commun, 398, pp. 613-618; Tombran-Tink, J., Chader, G.G., Johnson, L.V., PEDF: A pigment epithelium-derived factor with potent neuronal differentiative activity (1991) Exp Eye Res, 53, pp. 411-414; Wakino, S., Kintscher, U., Kim, S., Yin, F., Hsueh, W.A., Law, R.E., Peroxisome proliferator-activated receptor γ ligands inhibit retinoblastoma phosphorylation and G 1 → S transition in vascular smooth muscle cells (2000) Journal of Biological Chemistry, 275 (29), pp. 22435-22441. , DOI 10.1074/jbc.M910452199; Wang, S.H., Lin, S.J., Chen, Y.H., Lin, F.Y., Shih, J.C., Wu, C.C., Late outgrowth endothelial cells derived from Wharton jelly in human umbilical cord reduce neointimal formation after vascular injury: Involvement of pigment epithelium-derived factor (2009) Arterioscler Thromb Vasc Biol, 29, pp. 816-822; Yamagishi, S.-I., Inagaki, Y., Nakamura, K., Abe, R., Shimizu, T., Yoshimura, A., Imaizumi, T., Pigment epithelium-derived factor inhibits TNF-α-induced interleukin-6 expression in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation (2004) Journal of Molecular and Cellular Cardiology, 37 (2), pp. 497-506. , DOI 10.1016/j.yjmcc.2004.04.007, PII S0022282804000926; Yamagishi, S.-I., Nakamura, K., Ueda, S., Kato, S., Imaizumi, T., Pigment epithelium-derived factor (PEDF) blocks angiotensin II signaling in endothelial cells via suppression of NADPH oxidase: A novel anti-oxidative mechanism of PEDF (2005) Cell and Tissue Research, 320 (3), pp. 437-445. , DOI 10.1007/s00441-005-1094-8; Yang, S.L., Chen, S.L., Wu, J.Y., Ho, T.C., Tsao, Y.P., Pigment epithelium-derived factor induces interleukin-10 expression in human macrophages by induction of PPAR gamma (2010) Life Sci, 87, pp. 26-35; Zhang, S.X., Wang, J.J., Gao, G., Shao, C., Mott, R., Ma, J.-X., Pigment epithelium-derived factor (PEDF) is an endogenous antiinflammatory factor (2006) FASEB Journal, 20 (2), pp. 323-325. , http://www.fasebj.org/cgi/reprint/20/2/323, DOI 10.1096/fj.05-4313fje",
year = "2012",
doi = "10.1016/j.biocel.2011.10.023",
language = "English",
volume = "44",
pages = "280--289",
journal = "International Journal of Biochemistry and Cell Biology",
issn = "1357-2725",
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}

TY - JOUR

T1 - Pigment epithelium-derived factor reduces the PDGF-induced migration and proliferation of human aortic smooth muscle cells through PPARγ activation

AU - Wang, Shu-Huei

AU - Liang, Chan-Jung

AU - Wu, Jiahn-Chun

AU - Huang, Jiuan-Jiuan

AU - Chien, Hsiung-Fei

AU - Tsai, Jaw-Shiun

AU - Yen, Yuh-Siu

AU - Tseng, Ying-Chih

AU - Lue, June-Horng

AU - Chen, Yuh-Lien

N1 - 被引用次數:6 Export Date: 16 March 2016 CODEN: IJBBF 通訊地址: Lue, J.-H.; Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan; 電子郵件: thomas@ntu.edu.tw 化學物質/CAS: cyclin dependent kinase 2, 141349-86-2; cyclin dependent kinase 4, 147014-97-9; pigment epithelium derived factor, 197980-93-1; Eye Proteins; Nerve Growth Factors; PPAR gamma; Platelet-Derived Growth Factor; Serpins; pigment epithelium-derived factor 參考文獻: Abe, R., Fujita, Y., Yamagishi, S., Shimizu, H., Pigment epithelium-derived factor prevents melanoma growth via angiogenesis inhibition (2008) Curr Pharm des, 14, pp. 3802-3809; Andres, V., Castro, C., Antiproliferative strategies for the treatment of vascular proliferative disease (2003) Curr Vasc Pharmacol, 1, pp. 85-98; Bardot, O., Aldridge, T.C., Latruffe, N., Green, S., PPAR-RXR heterodimer activates a peroxisome proliferator response element upstream of the bifunctional enzyme gene (1993) Biochemical and Biophysical Research Communications, 192 (1), pp. 37-45. , DOI 10.1006/bbrc.1993.1378; Benson, S., Wu, J., Padmanabhan, S., Kurtz, T.W., Pershadsingh, H.A., Peroxisome proliferator-activated receptor (PPAR)-γ expression in human vascular smooth muscle cells: Inhibition of growth, migration, and c-fos expression by the peroxisome proliferator-activated receptor (PPAR)-γ activator troglitazone (2000) American Journal of Hypertension, 13 (1), pp. 74-82. , DOI 10.1016/S0895-7061(99)00148-X, PII S089570619900148X; Bishop-Bailey, D., Hla, T., Endothelial cell apoptosis induced by the peroxisome proliferator- activated receptor (PPAR) ligand 15-deoxy-Delta12, 14-prostaglandin J2 (1999) J Biol Chem, 274, pp. 17042-17048; Broadhead, M.L., Dass, C.R., Choong, P.F., Systemically administered PEDF against primary and secondary tumours in a clinically relevant osteosarcoma model (2011) Br J Cancer, pp. 1-9; Charron, T., Nili, N., Strauss, B.H., The cell cycle: A critical therapeutic target to prevent vascular proliferative disease (2006) Canadian Journal of Cardiology, 22 (SUPPL. B), pp. 41B-55B; Collino, M., Patel, N.S.A., Lawrence, K.M., Collin, M., Latchman, D.S., Yaqoob, M.M., Thiemermann, C., The selective PPARγ antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion (2005) Kidney International, 68 (2), pp. 529-536. , DOI 10.1111/j.1523-1755.2005.00430.x, PII 4494622; Dawson, D.W., Volpert, O.V., Gillis, P., Crawford, S.E., Xu, H.-J., Benedict, W., Bouck, N.P., Pigment epithelium-derived factor: A potent inhibitor of angiogenesis (1999) Science, 285 (5425), pp. 245-248. , DOI 10.1126/science.285.5425.245; Ek, E.T.H., Dass, C.R., Choong, P.F.M., Pigment epithelium-derived factor: A multimodal tumor inhibitor (2006) Molecular Cancer Therapeutics, 5 (7), pp. 1641-1646. , DOI 10.1158/1535-7163.MCT-06-0107; Ferns, G.A.A., Raines, E.W., Sprugel, K.H., Motani, A.S., Reidy, M.A., Ross, R., Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF (1991) Science, 253 (5024), pp. 1129-1132; Fujimura, T., Yamagishi, S., Ueda, S., Fukami, K., Shibata, R., Matsumoto, Y., Administration of pigment epithelium-derived factor (PEDF) reduces proteinuria by suppressing decreased nephrin and increased VEGF expression in the glomeruli of adriamycin-injected rats (2009) Nephrol Dial Transplant, 24, pp. 1397-1406; Ghosh, S.S., Gehr, T.W.B., Ghosh, S., Fakhry, I., Sica, D.A., Lyall, V., Schoolwerth, A.C., PPARγ ligand attenuates PDGF-induced mesangial cell proliferation: Role of MAP kinase (2003) Kidney International, 64 (1), pp. 52-62. , DOI 10.1046/j.1523-1755.2003.00054.x; Goetze, S., Xi, X.-P., Kawano, H., Gotlibowski, T., Fleck, E., Hsueh, W.A., Law, R.E., PPARγ-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells (1999) Journal of Cardiovascular Pharmacology, 33 (5), pp. 798-806. , DOI 10.1097/00005344-199905000-00018; Hamblin, M., Chang, L., Fan, Y., Zhang, J., Chen, Y.E., PPARs and the cardiovascular system (2009) Antioxid Redox Signal, 11, pp. 1415-1452; Hirsch, J., Johnson, C.L., Nelius, T., Kennedy, R., Riese, W., Filleur, S., PEDF inhibits IL8 production in prostate cancer cells through PEDF receptor/phospholipase A2 and regulation of NF κb and PPARγ (2011) Cytokine, 55, pp. 202-210; Hoshina, D., Abe, R., Yamagishi, S.I., Shimizu, H., The role of PEDF in tumor growth and metastasis (2010) Curr Mol Med, 10, pp. 292-295; Ho, T.C., Chen, S.L., Yang, Y.C., Liao, C.L., Cheng, H.C., Tsao, Y.P., PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells (2007) Cardiovasc Res, 76, pp. 213-223; Ho, T.C., Yang, Y.C., Chen, S.L., Kuo, P.C., Sytwu, H.K., Cheng, H.C., Pigment epithelium-derived factor induces THP-1 macrophage apoptosis and necrosis by the induction of the peroxisome proliferator-activated receptor gamma (2008) Mol Immunol, 45, pp. 898-909; Jiang, H.Y., Petrovas, C., Sonenshein, G.E., Relb-p50 NF-κB complexes are selectively induced by cytomegalovirus immediate-early protein 1: Differential regulation of Bcl-x L promoter activity by NF-κB family members (2002) Journal of Virology, 76 (11), pp. 5737-5747. , DOI 10.1128/JVI.76.11.5737-5747.2002; Law, R.E., Goetze, S., Xi, X.-P., Jackson, S., Kawano, Y., Demer, L., Fishbein, M.C., Hsueh, W.A., Expression and function of PPARγ in rat and human vascular smooth muscle cells (2000) Circulation, 101 (11), pp. 1311-1318; Law, R.E., Meehan, W.P., Xi, X.-P., Graf, K., Wuthrich, D.A., Coats, W., Faxon, D., Hsueh, W.A., Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia (1996) Journal of Clinical Investigation, 98 (8), pp. 1897-1905; Marx, N., Schonbeck, U., Lazar, M.A., Libby, P., Plutzky, J., Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells (1998) Circulation Research, 83 (11), pp. 1097-1103; Nakamura, K., Yamagishi, S.-I., Matsui, T., Yoshida, T., Takenaka, K., Jinnouchi, Y., Yoshida, Y., Imaizumi, T., Pigment epithelium-derived factor inhibits neointimal hyperplasia after vascular injury by blocking NADPH oxidase-mediated reactive oxygen species generation (2007) American Journal of Pathology, 170 (6), pp. 2159-2170. , DOI 10.2353/ajpath.2007.060838; Notari, L., Baladron, V., Aroca-Aguilar, J.D., Balko, N., Heredia, R., Meyer, C., Notario, P.M., Becerra, S.P., Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor (2006) Journal of Biological Chemistry, 281 (49), pp. 38022-38037. , http://www.jbc.org/cgi/reprint/281/49/38022, DOI 10.1074/jbc.M600353200; Ross, R., The pathogenesis of atherosclerosis: A perspective for the 1990 (1993) Nature, 362, pp. 801-809; Sata, M., Maejima, Y., Adachi, F., Fukino, K., Saiura, A., Sugiura, S., A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia (2000) J Mol Cell Cardiol, 32, pp. 2097-2104; Takenaka, K., Yamagishi, S.-i., Matsui, T., Nakamura, K., Jinnouchi, Y., Yoshida, Y., Ueda, S.-i., Imaizumi, T., Pigment epithelium-derived factor (PEDF) administration inhibits occlusive thrombus formation in rats: A possible participation of reduced intraplatelet PEDF in thrombosis of acute coronary syndromes (2008) Atherosclerosis, 197 (1), pp. 25-33. , DOI 10.1016/j.atherosclerosis.2007.07.041, PII S002191500700473X; Tan, M.L., Choong, P.F., Dass, C.R., Anti-chondrosarcoma effects of PEDF mediated via molecules important to apoptosis, cell cycling, adhesion and invasion (2010) Biochem Biophys Res Commun, 398, pp. 613-618; Tombran-Tink, J., Chader, G.G., Johnson, L.V., PEDF: A pigment epithelium-derived factor with potent neuronal differentiative activity (1991) Exp Eye Res, 53, pp. 411-414; 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PY - 2012

Y1 - 2012

N2 - Our previous study demonstrated that pigment epithelium-derived factor (PEDF) plays an important role in the proliferation and migration of human aortic smooth muscle cells (HASMCs). In the present study, we examined whether PEDF inhibited platelet-derived growth factor (PDGF)-stimulated HASMC migration and proliferation. PEDF dose-dependently reduced PDGF-induced HASMC migration and proliferation in vitro and also arrested cell cycle progression in the G0/G1 phase, and this was associated with decreased expression of cyclin D1, cyclin E, CDK2, CDK4, and p21 Cip1 and increased expression of the cyclin-dependent kinase inhibitor p27 Kip1. The antiproliferative and antimigratory effects of PEDF were partially blocked by the PPARγ antagonist GW9662, but not by the PPARα antagonist MK886. In in vivo studies, the femoral artery of C57BL/6 mice was endothelial-denuded and the mice injected intravenously with PEDF or vehicle. After 2 weeks, both the neointima/media area ratio and cell proliferation (proliferating cell nuclear antigen-positive cells) in the neointima were significantly reduced and again these effects were partially reversed by GW9662 pretreatment. Our data show that PEDF increases PPARγ activation, preventing entry of HASMCs into the cell cycle in vitro and reducing the neointimal area and cell proliferation in the neointima in vivo. Thus, PEDF may represent a safe and effective novel target for the prevention and treatment of vascular proliferative diseases. © 2011 Elsevier Ltd. All rights reserved.

AB - Our previous study demonstrated that pigment epithelium-derived factor (PEDF) plays an important role in the proliferation and migration of human aortic smooth muscle cells (HASMCs). In the present study, we examined whether PEDF inhibited platelet-derived growth factor (PDGF)-stimulated HASMC migration and proliferation. PEDF dose-dependently reduced PDGF-induced HASMC migration and proliferation in vitro and also arrested cell cycle progression in the G0/G1 phase, and this was associated with decreased expression of cyclin D1, cyclin E, CDK2, CDK4, and p21 Cip1 and increased expression of the cyclin-dependent kinase inhibitor p27 Kip1. The antiproliferative and antimigratory effects of PEDF were partially blocked by the PPARγ antagonist GW9662, but not by the PPARα antagonist MK886. In in vivo studies, the femoral artery of C57BL/6 mice was endothelial-denuded and the mice injected intravenously with PEDF or vehicle. After 2 weeks, both the neointima/media area ratio and cell proliferation (proliferating cell nuclear antigen-positive cells) in the neointima were significantly reduced and again these effects were partially reversed by GW9662 pretreatment. Our data show that PEDF increases PPARγ activation, preventing entry of HASMCs into the cell cycle in vitro and reducing the neointimal area and cell proliferation in the neointima in vivo. Thus, PEDF may represent a safe and effective novel target for the prevention and treatment of vascular proliferative diseases. © 2011 Elsevier Ltd. All rights reserved.

KW - Cell cycle

KW - Neointimal hyperplasia

KW - PEDF

KW - PPARγ

KW - Proliferation

KW - 2 chloro 5 nitrobenzanilide

KW - cyclin D1

KW - cyclin dependent kinase 2

KW - cyclin dependent kinase 4

KW - cyclin dependent kinase inhibitor 1

KW - cyclin dependent kinase inhibitor 1B

KW - cyclin E

KW - cycline

KW - peroxisome proliferator activated receptor gamma

KW - pigment epithelium derived factor

KW - platelet derived growth factor

KW - animal experiment

KW - animal model

KW - animal tissue

KW - antiproliferative activity

KW - aorta media

KW - artery intima proliferation

KW - article

KW - blood vessel injury

KW - cell cycle G0 phase

KW - cell cycle progression

KW - cell migration

KW - cell proliferation

KW - concentration response

KW - controlled study

KW - femoral artery

KW - G1 phase cell cycle checkpoint

KW - human

KW - human cell

KW - male

KW - mouse

KW - neointima

KW - nonhuman

KW - protein expression

KW - smooth muscle fiber

KW - Western blotting

KW - Animals

KW - Aorta

KW - Cell Cycle

KW - Cell Movement

KW - Cell Proliferation

KW - Eye Proteins

KW - Humans

KW - Mice

KW - Muscle, Smooth, Vascular

KW - Neointima

KW - Nerve Growth Factors

KW - Platelet-Derived Growth Factor

KW - PPAR gamma

KW - Serpins

KW - Mus

U2 - 10.1016/j.biocel.2011.10.023

DO - 10.1016/j.biocel.2011.10.023

M3 - Article

VL - 44

SP - 280

EP - 289

JO - International Journal of Biochemistry and Cell Biology

JF - International Journal of Biochemistry and Cell Biology

SN - 1357-2725

IS - 2

ER -