New targets for PPARgamma in the vessel wall: implications for restenosis.
Peroxisome proliferator-activated receptor {gamma} (PPARgamma), the nuclear receptor that binds the insulin-sensitizing thiazolidinediones (TZDs), is prominently upregulated in intimal vascular smooth muscle cells (VSMC) after mechanical injury to the vessel wall. Several TZD PPARgamma ligands have been shown to inhibit neointima formation in both normal and insulin-resistant vasculature. The suppression of intimal hyperplasia by TZD PPARgamma ligands probably results from their activity to inhibit VSMC growth and promote apoptosis. TZDs prevent VSMC proliferation by blocking the activity of regulatory proteins, such as phosphorylation of the retinoblastoma protein (Rb). Rb functions as a G(1) gatekeeper by controlling S phase gene expression mediated by the E2F transcription factor. Consistent with their effect on Rb phosphorylation, PPARgamma ligands inhibit the mitogenic induction of minichromosome maintenance (MCM) proteins 6 and 7, two E2F-regulated S phase genes essential for DNA replication. PPARgamma ligands also induced apoptosis in VSMC, which correlated with a potent induction of GADD45, a gene implicated in controlling cell growth and survival. A constitutively active form of PPARgamma targeted the same cell cycle regulators as did PPARgamma ligands, consistent with a nuclear-receptor-dependent mechanism of action. This review will summarize mechanisms through which PPARgamma modulates VSMC proliferation and apoptosis suggesting that PPARgamma itself is a novel important regulator of cell cycle and apoptosis and may provide a new therapeutic approach to prevent restenosis.
Bruemmer
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Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington, KY, USA. Dennis.Bruemmer@uky.edu
Blaschke
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Law
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D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D023903:Coronary Restenosis / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D017539:Tunica Intima / Q000378:metabolism; D000097642:GADD45 Proteins
D047908:Intracellular Signaling Peptides and Proteins; D047495:PPAR gamma; D011506:Proteins; D000097642:GADD45 Proteins