P178	Induction of the tumor suppressor p16INK4A (p16) gene by thiazolidinedione PPARγ agonists in atherosclerotic plaques.
1F.Gizard, 1A.Tailleux, 1C.Fieve, 2L.Milla, 3N.Marx, 1B.Staels
1U545 INSERM, Département dAthérosclérose, Institut Pasteur de Lille et Faculté de Pharmacie, Université Lille II, Lille, FR; 2Genfit, Parc Eurasanté, Loos, FR; 3Department Internal Medicine II, Ulm University, Ulm, DE.

The «cyclin-dependent kinase inhibitor» (CDKI) and tumor suppressor p16INK4A (p16) has recently been shown to mediate the growth-inhibitory effects of fibrate PPARα agonists on smooth muscle cells (SMCs) in vitro and in a mouse model of restenosis. Here we show that p16 is also induced by thiazolidinedione (TZD) PPARγ agonists, anti-diabetic drugs used in the treatment of type II diabetes which also prevent vascular intimal hyperplasia development. First, in vitro analyses indicated that TZD-activated PPARγ up-regulates p16 promoter activity through the PPARα-responsive DR1-like site localized at nucleotide -1023 of the promoter. As a consequence, p16 mRNA and protein levels increase in SMCs following TZD treatment. Second, in vivo analyses performed in apoE-deficient and human apoE2 knock-in mice, two mouse models of atherosclerosis, indicate that both PPARγ and p16 gene expression are increased at an early stage of atherosclerotic lesion development in the aortic sinus, suggesting that the PPARγ/p16 pathway may play a role in the atherogenic process. Finally, results from a prospective carotid endarterectomy clinical study demonstrate that short-duration (4-weeks) TZD treatment results in a significant increase of p16 gene expression in carotid artery atherosclerotic plaques. Immuno-histological analyses further indicated a decrease of SMC number associated with an increase of p16 staining in these atheroclerotic plaques. Taken together, these data identify p16 as a PPARγ target gene in atherosclerotic lesions, where it may participate in the atheroprotective affects of TZD treatment.

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