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(Circulation Research. 2004;95:e110.)
© 2004 American Heart Association, Inc.

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Liver X Receptor Agonists Suppress Vascular Smooth Muscle Cell Proliferation and Inhibit Neointima Formation in Balloon-Injured Rat Carotid Arteries

Florian Blaschke, Olli Leppanen, Yasunori Takata, Evren Caglayan, Joey Liu, Michael C. Fishbein, Kai Kappert, Keiichi I. Nakayama, Alan R. Collins, Eckart Fleck, Willa A. Hsueh, Ronald E. Law, Dennis Bruemmer

From the Division of Endocrinology, Diabetes, and Hypertension (F.B., Y.T., E.C., J.L., W.A.H., R.E.L.) and the Department of Pathology (M.C.F.), David Geffen School of Medicine, University of California, Los Angeles; Department of Medicine/Cardiology (F.B., E.F.), German Heart Institute, Berlin, Germany; Division of Vascular Surgery (O.L.), University Hospital, Uppsala, Sweden; Department of Pathology-Oncology (K.K.), Karolinska Institute, Stockholm, Sweden; Department of Molecular and Cellular Biology (K.I.N.), Kyushu University, Fukuoka, Japan; and Division of Endocrinology and Molecular Medicine (D.B.), University of Kentucky College of Medicine, Lexington. Present address for R.E.L. is Takeda Pharmaceuticals of North America, Lincolnshire, Ill.

Correspondence and requests for reprints to Dennis Bruemmer, MD, University of Kentucky College of Medicine, Department of Internal Medicine, Division of Endocrinology and Molecular Medicine, Wethington Health Sciences Bldg, Rm 575, 900 S Limestone St, Lexington, KY 40536-0200. E-mail Dennis.Bruemmer{at}uky.edu

The liver X receptors and ß (LXR and LXRß) are important regulators of cholesterol homeostasis in liver and macrophages. Synthetic LXR ligands prevent the development of atherosclerosis in murine models; however, the potential functional relevance of LXRs in vascular smooth muscle cells (VSMCs) has not been investigated. In the present study, we demonstrate that LXRs are expressed and functional in primary human coronary artery VSMCs (CASMCs). LXR ligands inhibited mitogen-induced VSMC proliferation and G₁S phase progression of the cell cycle. Inhibition of G₁ exit by LXR ligands was accompanied by a dose-dependent inhibition of retinoblastoma protein (Rb) phosphorylation, which functions as the key switch for G₁S cell cycle progression. LXR ligands suppressed mitogen-induced degradation of the cyclin-dependent kinase inhibitor p27^Kip1, attenuated cyclin D1 and cyclin A expression, and inhibited the expression of S phase-regulatory minichromosome maintenance protein 6. Stabilization of p27^kip1 by LXR ligands was mediated by supressing the transcriptional activation of the S phase kinase–associated protein 2 (Skp2), an F-box protein that targets p27^Kip1 for degradation. Inhibition of Rb phosphorylation and G₁S cell cycle progression by LXR ligands was reversed in VSMCs overexpressing Skp2, indicating that Skp2 as an upstream regulator of p27^Kip1 degradation plays a central role in LXR ligand–mediated inhibition of VSMC proliferation. Furthermore, adenovirus-mediated overexpression of the S phase transcription factor E2F, which is released after Rb phosphorylation, reversed the inhibitory effect of LXR ligands on VSMC proliferation and S phase gene expression, suggesting that the primary mechanisms by which LXR ligands inhibit VSMC proliferation occur upstream of Rb phosphorylation. Finally, neointima formation in a model of rat carotid artery balloon injury was significantly attenuated after treatment with the LXR ligand T1317 compared with vehicle-treated animals. These data demonstrate that LXR ligands inhibit VSMC proliferation and neointima formation after balloon injury and suggest that LXR ligands may constitute a novel therapy for proliferative vascular diseases. The full text of this article is available online at http://circres.ahajournals.org.

Key Words: vascular smooth muscle cell • liver X receptor • arterial injury

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