Peroxisome Proliferator-activated Receptor δ Is Up-regulated during Vascular Lesion Formation and Promotes Post-confluent Cell Proliferation in Vascular Smooth Muscle Cells

Abstract

Although peroxisome proliferator-activated receptor (PPAR) δ is widely expressed in many tissues, the role of PPARδ is poorly understood. In this study, we report that PPARδ was up-regulated in vascular smooth muscle cells (VSMC) during vascular lesion formation. By using Northern blot analysis, we demonstrated that PPARδ was increased by 3–4-fold in VSMC treated with platelet-derived growth factor (PDGF) (20 ng/ml). In addition, PDGF-induced PPARδ mRNA expression neither needs de novo protein synthesis nor affects the stability of PPARδ mRNA in VSMC. Preincubation of VSMC with phosphatidylinositol 3-kinase inhibitor (LY294002, 50 μmol/liter) or infection of VSMC with an adenovirus carrying the gene for a dominant negative form of Akt abrogated PDGF-induced PPARδ mRNA expression, suggesting that phosphatidylinositol 3-kinase/Akt signaling pathway is involved in the regulation of PDGF-induced PPARδ mRNA expression in VSMC. To explore the role of PPARδ in VSMC, we generated rat vascular smooth muscle cells (A7r5) stably overexpressing PPARδ and the control green fluorescent protein. Overexpression of PPARδ in VSMC increased post-confluent cell proliferation by increasing the cyclin A and CDK2 as well as decreasing p57kip2. Taken together, the results suggest that PPARδ plays an important role in the pathology of diseases associated with VSMC proliferation, such as primary atherosclerosis and restenosis. Although peroxisome proliferator-activated receptor (PPAR) δ is widely expressed in many tissues, the role of PPARδ is poorly understood. In this study, we report that PPARδ was up-regulated in vascular smooth muscle cells (VSMC) during vascular lesion formation. By using Northern blot analysis, we demonstrated that PPARδ was increased by 3–4-fold in VSMC treated with platelet-derived growth factor (PDGF) (20 ng/ml). In addition, PDGF-induced PPARδ mRNA expression neither needs de novo protein synthesis nor affects the stability of PPARδ mRNA in VSMC. Preincubation of VSMC with phosphatidylinositol 3-kinase inhibitor (LY294002, 50 μmol/liter) or infection of VSMC with an adenovirus carrying the gene for a dominant negative form of Akt abrogated PDGF-induced PPARδ mRNA expression, suggesting that phosphatidylinositol 3-kinase/Akt signaling pathway is involved in the regulation of PDGF-induced PPARδ mRNA expression in VSMC. To explore the role of PPARδ in VSMC, we generated rat vascular smooth muscle cells (A7r5) stably overexpressing PPARδ and the control green fluorescent protein. Overexpression of PPARδ in VSMC increased post-confluent cell proliferation by increasing the cyclin A and CDK2 as well as decreasing p57kip2. Taken together, the results suggest that PPARδ plays an important role in the pathology of diseases associated with VSMC proliferation, such as primary atherosclerosis and restenosis. The peroxisome proliferator-activated receptors (PPARs) 1The abbreviations used are: PPARperoxisome proliferator-activated receptorPI3-kinasephosphatidylinositol 3-kinaseVSMCsvascular smooth muscle cellsPDGFplatelet-derived growth factorPGIprostacyclin IcPGIcarbaprostacyclin IDMEMDulbecco's modified Eagle's mediumFBSfetal bovine serumRASMCsrat aortic smooth muscle cellsRTreverse transcriptaseGAPDHglyceraldehyde-3-phosphate dehydrogenasentnucleotideIRESinternal ribosomal entry sequenceFACSfluorescence-activated cell sorterGFPgreen fluorescent proteinCDKcyclin-dependent kinaseERKextracellular signal-regulated kinaseMEKmitogen-activated protein kinase/ERK kinase including α, δ/β, and γ are members of the superfamily of nuclear receptors. The general structural features of the family include a central DNA-binding domain and a carboxyl-terminal domain that mediates ligand binding, dimerization, and transactivation functions. PPARs function as a heterodimer with retinoid X receptors, another member of this family, to bind to the PPAR-responsive element, a DR1 element, which is a direct repeat of two similar hexanucleotide (5′-AGGTCA-3′) half-sites separated by one nucleotide on its target genes (1.Kliewer S.A. Umesono K. Noonan D.J. Heyman R.A. Evans R.M. Nature. 1992; 358: 771-774Crossref PubMed Scopus (1521) Google Scholar). In the presence of both PPAR- and retinoid X receptor-specific ligands, this type of interaction confers synergistic activation of target genes (1.Kliewer S.A. Umesono K. Noonan D.J. Heyman R.A. Evans R.M. Nature. 1992; 358: 771-774Crossref PubMed Scopus (1521) Google Scholar). peroxisome proliferator-activated receptor phosphatidylinositol 3-kinase vascular smooth muscle cells platelet-derived growth factor prostacyclin I carbaprostacyclin I Dulbecco's modified Eagle's medium fetal bovine serum rat aortic smooth muscle cells reverse transcriptase glyceraldehyde-3-phosphate dehydrogenase nucleotide internal ribosomal entry sequence fluorescence-activated cell sorter green fluorescent protein cyclin-dependent kinase extracellular signal-regulated kinase mitogen-activated protein kinase/ERK kinase PPARα is highly expressed in the liver, muscle, kidney, and heart, where it stimulates the β-oxidative degradation of fatty acids. PPARγ is most abundantly expressed in fat cells, large intestine, and cells of the monocyte lineage (2.Lemberger T. Braissant O. Juge-Aubry C. Keller H. Saladin R. Staels B. Auwerx J. Burger A.G. Meier C.A. Wahli W. Ann. N. Y. Acad. Sci. 1996; 804: 231-251Crossref PubMed Scopus (155) Google Scholar). PPARγ has been linked to adipocyte differentiation and insulin sensitivity. Both PPARα and PPARγ are expressed in monocytes/macrophages, endothelial cells, and vascular smooth muscle cells (VSMC) in both medial and intimal layers. Activation of PPARα has been found to inhibit VSMC production of inflammatory factors (3.Staels B. Koenig W. Habib A. Merval R. Lebret M. Torra I.P. Delerive P. Fadel A. Chinetti G. Fruchart J.C. Najib J. Maclouf J. Tedgui A. Nature. 1998; 393: 790-793Crossref PubMed Scopus (1056) Google Scholar), although activation of PPARγ has been reported to decrease both VSMC proliferation (4.Law R.E. Goetze S. Xi X.P. Jackson S. Kawano Y. Demer L. Fishbein M.C. Meehan W.P. Hsueh W.A. Circulation. 2000; 101: 1311-1318Crossref PubMed Scopus (424) Google Scholar) and matrix production after vascular injury (5.Fu M. Zhang J. Zhu X. Myles D.E. Willson T.M. Liu X. Chen Y.E. J. Biol. Chem. 2001; 276: 45888-45894Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). Therefore, PPARα and PPARγ are emerging as important determinants of vascular function and structure (6.Rosen E.D. Spiegelman B.M. J. Biol. Chem. 2001; 276: 37731-37734Abstract Full Text Full Text PDF PubMed Scopus (1080) Google Scholar, 7.Bishop-Bailey D. Br. J. Pharmacol. 2000; 129: 823-834Crossref PubMed Scopus (323) Google Scholar, 8.Kersten S. Desvergne B. Wahli W. Nature. 2000; 405: 421-424Crossref PubMed Scopus (1665) Google Scholar). Although PPARδ (also known as PPARβ and NUC-1) is widely expressed in many tissues, the physiological or pathophysiological roles of PPARδ are unclear. With no connection to important clinical manifestations, along with the lack of marketed PPARδ-specific ligands, the research to define PPARδ function has been hampered for many years. However, PPARδ has recently been linked to colon cancer proliferation (9.He T.C. Chan T.A. Vogelstein B. Kinzler K.W. Cell. 1999; 99: 335-345Abstract Full Text Full Text PDF PubMed Scopus (1034) Google Scholar, 10.Gupta R.A. Tan J. Krause W.F. Geraci M.W. Willson T.M. Dey S.K. DuBois R.N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13275-13280Crossref PubMed Scopus (358) Google Scholar, 11.Park B.H. Vogelstein B. Kinzler K.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 2598-2603Crossref PubMed Scopus (224) Google Scholar), preadipocyte proliferation (12.Hansen J.B. Zhang H. Rasmussen T.H. Petersen R.K. Flindt E.N. Kristiansen K. J. Biol. Chem. 2001; 276: 3175-3182Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 13.Jehl-Pietri C. Bastie C. Gillot I. Luquet S. Grimaldi P.A. Biochem. J. 2000; 350: 93-98Crossref PubMed Scopus (61) Google Scholar), macrophage lipid accumulation (14.Vosper H. Patel L. Graham T. Khoudoli G.A. Hill A. Macphee C.H. Pinto I. Smith S.A. Suckling K.E. Wolf C.R. Palmer C.N. J. Biol. Chem. 2001; 276: 44258-44265Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar), and embryo implantation (15.Lim H. Gupta R.A. Ma W.G. Paria B.C. Moller D.E. Morrow J.D. DuBois R.N. Trzaskos J. M., Dey S.K. Genes Dev. 1999; 13: 1561-1574Crossref PubMed Scopus (536) Google Scholar). Interestingly, prostacyclin (PGI2), which is the natural ligand of PPARδ, is the characteristic prostanoid released by vascular endothelial and smooth muscle cells in response to stimulation by cytokines such as tumor necrosis factor α (16.Baenziger N.L. Becherer P.R Majerus P.W. Cell. 1979; 16: 967-974Abstract Full Text PDF PubMed Scopus (134) Google Scholar). Taken together, we hypothesize that PPARδ plays an important role in VSMC proliferation. VSMC proliferation is the key component of vasculoproliferative diseases including atherosclerosis, restenosis, and vein-graft failure (17.Braun-Dullaeus R.C. Mann M.J. Dzau V.J. Circulation. 1998; 98: 82-89Crossref PubMed Scopus (304) Google Scholar, 18.Sriram V. Patterson C. Circulation. 2001; 103: 2414-2419Crossref PubMed Scopus (89) Google Scholar). Cytokines and growth factors such as tumor necrosis factor α and PDGF participate in these processes (19.Libby P. Vasc. Med. 1998; 3: 225-229Crossref PubMed Scopus (75) Google Scholar). In eukaryotic cells, the commitment to divide is made in the G1 phase of the cell cycle in response to various stimuli, including growth factors. The D- and E-type cyclins in combination with cyclin-dependent kinases (CDKs) regulate passage through the G1 phase (20.Sherr C.J. Roberts J.M. Genes Dev. 1995; 9: 1149-1163Crossref PubMed Scopus (3215) Google Scholar, 21.Sherr C.J. DePinho R.A. Cell. 2000; 102: 407-410Abstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar). Overexpression of cyclin D or E can shorten G1 phase (22.Resnitzky D. Gossen M. Bujard H. Reed S.I. Mol. Cell. Biol. 1994; 14: 1669-1679Crossref PubMed Scopus (990) Google Scholar, 23.Kato J.Y. Sherr C.J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 11513-11517Crossref PubMed Scopus (211) Google Scholar, 24.Ohtsubo M. Roberts J.M. Science. 1993; 259: 1908-1912Crossref PubMed Scopus (662) Google Scholar), suggesting that the cyclin family is critical for progression through G1 phase. In this report, we document that PPARδ is up-regulated in VSMC during vascular lesion formation, and we demonstrate that PDGF stimulation increases PPARδ expression by 3–4-fold in VSMC. We also show that overexpression of PPARδ in VSMC promotes the proliferation of confluent cells by increasing the cyclin A and CDK2 but decreased p57kip2. Platelet-derived growth factor (PDGF) BB, and and medium and The rat aortic smooth muscle cells as T.A. PubMed Google Scholar). The by α smooth muscle using used in and aortic smooth muscle cells The cells in smooth muscle cell growth growth growth 50 50 and bovine of aortic smooth muscle cells to and made by serum for The and the of The D was to the cells after stimulation for The was to the cells the with The rat vascular smooth muscle cell was rat injury was and The was with an to as and the was as control Google Scholar). with an of and to with and after The and in with a The with The was in a and by a on an of by using was to through to the was to the by an generated by using the and with for and with for The using the of cell was to and to in and for with PPARδ cyclin A cyclin E or The with was by the to the The expression of PPARδ mRNA in rat by the and rat and after The of was the medial by for used for and to to rat PPARδ used for The results by adenovirus carrying the gene for a dominant negative form of Akt was K. W. Y. T. H. W. C. M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The was as M. Zhu X. Zhang J. H. W. J. Chen Y.E. 2001; PubMed Scopus Google Scholar). In this study, with adenovirus The cells to after The PPARδ was a Grimaldi C. Luquet S. D. C. Grimaldi P.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of of cells and was by using the expression as X. Y. R.A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). the PPARδ was the of the internal ribosomal entry sequence which a gene in the We cells with in the presence of of for after the cells by a to A of cells by was used for this the we generated the control cells To the growth and cell cycle and cells, the cells in a of cells well in The medium was The of cells was by the after and was for was to cell cycle and the post-confluent cells for with and treated with A and for The cell was with for and with for by using a on a was using the was a of by of and are as The for was To PPARδ is expressed in VSMC, we the expression of PPARδ in both and rat aortic smooth muscle By using both Northern blot and blot we demonstrated that PPARδ is expressed in both and rat VSMC document that PPARδ is expressed in vascular smooth muscle cells as J.M. Vasc. Biol. 1999; PubMed Google Scholar). To explore the role of PPARδ in VSMC, we the PPARδ expression and using the results that in this was associated with a in PPARδ expression with control To define the expression of PPARδ in we using and rat in the of PPARδ mRNA expression in rat was that in rat after In addition, the PPARδ mRNA increased and and after that PPARδ function as an important of vascular lesion formation. was to document that PPARδ is up-regulated during vascular lesion formation. To PDGF is for the of PPARδ expression in the treated with PDGF for and Northern blot that the of PPARδ mRNA increased a and the control for after PDGF stimulation The response to PDGF-induced PPARδ mRNA expression was of PDGF in the expression of PPARδ mRNA was up-regulated in a A was a PDGF as as increases a of results that PDGF can PPARδ gene expression in VSMC. The of PDGF on PPARδ protein was also by blot treated with PDGF for and by The which by PDGF-induced of PPARδ, was increased as as and a The was decreased and and increased and a results demonstrate that PDGF PPARδ protein in a in In similar results in aortic vascular smooth muscle cells by both Northern blot and blot To PPARδ mRNA stability to PDGF-induced PPARδ gene expression, we the of PPARδ mRNA in Northern blot with the of D after of PDGF (20 or In the of PPARδ mRNA was was no and cells To de novo protein synthesis is for PDGF-induced PPARδ gene expression, we PPARδ mRNA treated with or PDGF (20 and in the presence or of for in the protein PPARδ mRNA after of PDGF suggesting that PDGF-induced PPARδ mRNA expression de novo protein To the signaling PDGF-induced PPARδ expression, we on the roles of the and mitogen-activated protein treated with PDGF for after with a inhibitor a kinase inhibitor or a inhibitor for in the of PDGF Although of mitogen-activated protein kinase the of PDGF-induced PPARδ expression by the of PPARδ expression in VSMC by However, of increased PDGF-induced PPARδ mRNA expression by To define the signaling pathway mediates PDGF-induced PPARδ gene expression in VSMC, we this signaling pathway by using adenovirus carrying the gene for a dominant negative form of of the pathway PDGF-induced PPARδ gene expression in However, PPARδ expression was by the control adenovirus infection in Taken together, these results the that PDGF-induced PPARδ gene expression is by a To the of Akt in PDGF-induced PPARδ expression in VSMC, we the PPARδ protein in the rat vascular smooth muscle cell (A7r5) that stably with a Akt control cells stably with a We found that PPARδ in was by blot but was in the control results that Akt is involved in the regulation of PPARδ expression in VSMC. We by the that the rat VSMC to PPARδ by Northern blot or blot of PPARδ expression cells and with the to in VSMC gene To PPARδ expression in the cells, expression used The cells an that a mRNA that was two and PPARδ A of cells or the control cells by was used for this was no in or and cells in cell to define the role of PPARδ in VSMC. To the of PPARδ overexpression in VSMC, we the of cell growth in both and cells by cell Although the growth of cells was similar to that of cells the cells cells after the cell cycle in and cells was by the cells and The of phase cells in was that in We also the of by serum in both and cells by both nuclear and was no and cells Taken together, these results suggest that PPARδ in VSMC is involved in cell proliferation. To the that PPARδ promotes VSMC we the cell cycle in both and cells by blot in the of cyclin A and CDK2 in cells that in cells in growth and the of CDK2 was in cells in cells after Interestingly, the of CDK2 was in cells in cells after but was no in cyclin E the two cell is that in are in by factors that cell and matrix PPARα and PPARγ are members of a family of nuclear factors that are emerging as important determinants of vascular function and Activation of PPARα has been found to inhibit VSMC production of inflammatory factors (3.Staels B. Koenig W. Habib A. Merval R. Lebret M. Torra I.P. Delerive P. Fadel A. Chinetti G. Fruchart J.C. Najib J. Maclouf J. Tedgui A. Nature. 1998; 393: 790-793Crossref PubMed Scopus (1056) Google Scholar). that the expression of PPARγ was up-regulated in intimal VSMC (4.Law R.E. Goetze S. Xi X.P. Jackson S. Kawano Y. Demer L. Fishbein M.C. Meehan W.P. Hsueh W.A. Circulation. 2000; 101: 1311-1318Crossref PubMed Scopus (424) Google Scholar), and activation of PPARγ has been found to decrease both VSMC proliferation S. U. S. Hsueh W.A. R.E. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and matrix production after vascular injury (5.Fu M. Zhang J. Zhu X. Myles D.E. Willson T.M. Liu X. Chen Y.E. J. Biol. Chem. 2001; 276: 45888-45894Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). Although it has been well that PPARα and PPARγ are important determinants of vascular function and the role of PPARδ in is poorly understood. In the we document that PPARδ is expressed in VSMC and up-regulated by and in rat and after Interestingly, J.M. Vasc. Biol. 1999; PubMed Google Scholar) that PPARδ expression was up-regulated by and was after with control to the by and for suggesting is a in PPARδ after A of PPARδ expression after injury is to this in the two In addition, are to the of this such as primary atherosclerosis, restenosis, and vein-graft failure are by the accumulation of intimal smooth muscle cell proliferation, and extracellular matrix (17.Braun-Dullaeus R.C. Mann M.J. Dzau V.J. Circulation. 1998; 98: 82-89Crossref PubMed Scopus (304) Google Scholar, 18.Sriram V. Patterson C. Circulation. 2001; 103: 2414-2419Crossref PubMed Scopus (89) Google Scholar). Cytokines and growth factors such as PDGF participate in these We that PDGF PPARδ expression in VSMC. we that PDGF PPARδ expression in a and in VSMC. that PPARδ is involved in VSMC proliferation during vascular lesion formation. PDGF is an important that mediates the of VSMC in the of vascular PDGF to its receptor on VSMC can signaling including and which the and the proliferation and of VSMC L. J. M.J. Cell. 1998; PubMed Scopus Google Scholar, J. H. A. Cell. 1996; PubMed Scopus Google Scholar). In the study, we demonstrated that PDGF-induced PPARδ mRNA expression was most of an of the stability of PPARδ mRNA the of PDGF to the degradation of PPARδ mRNA in VSMC. In addition, PDGF-induced PPARδ mRNA expression de novo protein synthesis the of protein synthesis inhibitor in VSMC PDGF-induced PPARδ Taken together, the suggest that in the PPARδ The PPARδ gene is of on J. K. L. A. C. J. Mol. Med. 2000; Google Scholar). To is known PPARδ The report on the regulation of PPARδ gene that are two on the (9.He T.C. Chan T.A. Vogelstein B. Kinzler K.W. Cell. 1999; 99: 335-345Abstract Full Text Full Text PDF PubMed Scopus (1034) Google Scholar). The of PPARδ by was as one of the involved in the of the regulation of the PPARδ gene such as of in the PPARδ PPARδ gene regulation but also that define the role of PPARδ in vasculoproliferative and Although this is the of the study, we an PPARδ gene and are to the in the PPARδ We that of the of PDGF-induced PPARδ expression in VSMC, although the used was and the results using with a dominant negative Akt The of PPARδ in cells stably with a Akt was M. X. Y. Taken together, these results the that PPARδ gene expression is by a signaling However, the inhibitor increased PDGF-induced PPARδ mRNA are to activation of the signaling pathway PDGF-induced PPARδ expression and to the and signaling in the regulation of PDGF-induced PPARδ expression in VSMC. Activation of signaling pathway PPARγ in a of PPARγ L. J. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. J.M. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In PPARα by pathway the PPARα C. A. A. Burger A.G. Meier C.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (160) Google Scholar). Interestingly, that PDGF PPARδ expression but also PPARδ are to PPARδ and to its Although we demonstrated that PDGF-induced PPARδ gene expression was by the it to the PPARδ target genes are PDGF stimulation in VSMC. However, it is to this the PPARδ gene VSMC been To the role of PPARδ in it to define the PPARδ target genes in VSMC. is using a to this many the lack of PPARδ-specific has hampered to define PPARδ has been reported that carbaprostacyclin a of is a PPARδ ligand B.M. Chen J. Evans R.M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). is a ligand that is the been can as a ligand for However, the of to PPARδ in VSMC is of the of this In or is to R.A. Tan J. Krause W.F. Geraci M.W. Willson T.M. Dey S.K. DuBois R.N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13275-13280Crossref PubMed Scopus (358) Google Scholar). To this is a to an in which is as the ligand for is the prostanoid released by both endothelial cells J. Biol. Chem. Full Text PDF PubMed Google Scholar) and VSMC (16.Baenziger N.L. Becherer P.R Majerus P.W. Cell. 1979; 16: 967-974Abstract Full Text PDF PubMed Scopus (134) Google Scholar) including M. M. R. N. M. Y. T. Sci. 1992; PubMed Scopus Google Scholar), we that a cell to the PPARδ function in VSMC. is important to that a report has the PPARδ with an and for PPARδ N.L. M.C. S.A. B.C. Willson T.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: PubMed Scopus Google Scholar). in the of PPARδ R.A. Tan J. Krause W.F. Geraci M.W. Willson T.M. Dey S.K. DuBois R.N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13275-13280Crossref PubMed Scopus (358) Google Scholar, 11.Park B.H. Vogelstein B. Kinzler K.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 2598-2603Crossref PubMed Scopus (224) Google Scholar) that PPARδ promotes colon cancer proliferation and preadipocyte proliferation (12.Hansen J.B. Zhang H. Rasmussen T.H. Petersen R.K. Flindt E.N. Kristiansen K. J. Biol. Chem. 2001; 276: 3175-3182Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 13.Jehl-Pietri C. Bastie C. Gillot I. Luquet S. Grimaldi P.A. Biochem. J. 2000; 350: 93-98Crossref PubMed Scopus (61) Google Scholar). In the study, we demonstrate that PDGF PPARδ expression, and PPARδ is up-regulated in during vascular lesion formation. We hypothesize that overexpression of PPARδ in VSMC is a to cell proliferation. results growth in cells the control cells after and no in growth and cell is with a report C. Bastie C. Gillot I. Luquet S. Grimaldi P.A. Biochem. J. 2000; 350: 93-98Crossref PubMed Scopus (61) Google Scholar) that PPARδ promotes post-confluent cell proliferation in In addition, suggest that can PPARδ with to the of cells to the growth VSMC proliferation is the component of vasculoproliferative injury results in the of growth factors and cytokines that VSMC to the cell cycle progression is on the expression and activation of cyclin-dependent kinases which form with the Activation of cyclin D cyclin D and cyclin CDK2 during G1 phase results in G1 cyclin-dependent kinase and are negative of the cell cycle by to and the activation of In this study, we demonstrated that cyclin A and CDK2 in that in with this the of in that in cells after in post-confluent VSMC proliferation by PPARδ Interestingly, the of CDK2 was in in cells after results are with C.J. Roberts J.M. Genes Dev. 1999; 13: PubMed Scopus Google Scholar, S. U. Liu S. M. T. Hsueh W.A. R.E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) that that and of function as during the G1 phase and as factors to of In we report that PPARδ is expressed in VSMC and up-regulated in during vascular lesion formation. In addition, we demonstrate that PDGF-induced PPARδ gene expression is by Overexpression of PPARδ in VSMC promotes the post-confluent cell proliferation. Taken together, results suggest that PPARδ plays an important role in the of vasculoproliferative such as primary atherosclerosis, restenosis, and vein-graft We and Grimaldi for for this