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(Circulation. 2002;106:1530.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Protective Function of Transcription Factor TR3 Orphan Receptor in Atherogenesis

Decreased Lesion Formation in Carotid Artery Ligation Model in TR3 Transgenic Mice

E. Karin Arkenbout, MD; Vivian de Waard, PhD; Maaike van Bragt, BSc; Tanja A.E. van Achterberg, BSc; Jos M. Grimbergen, BSc; Bruno Pichon, PhD; Hans Pannekoek, PhD; Carlie J.M. de Vries, PhD

From the Department of Biochemistry (E.K.A., V.d.W., M.v.B., T.A.E.v.A., H.P., C.J.M.d.V.), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Gaubius Laboratory (J.M.G.), Leiden, the Netherlands; and ULB-IBMM-IRIBHN (B.P.), Gosselies, Belgium.

Correspondence to C.J.M. de Vries, PhD, Department of Biochemistry, Academic Medical Center, K1-163, Meibergdreef 15, 1105 AZ Amsterdam, Netherlands. E-mail c.j.devries@ amc.uva.nl

Background— Smooth muscle cells (SMCs) play a key role in intimal thickening in atherosclerosis and restenosis. The precise signaling pathways by which the proliferation of SMCs is regulated are largely unknown. The TR3 orphan receptor, the mitogen-induced nuclear orphan receptor (MINOR), and the nuclear receptor of T cells (NOT) are a subfamily of transcription factors belonging to the nuclear receptor superfamily and are induced in activated SMCs. In this study, we investigated the role of these transcription factors in SMC proliferation in atherogenesis.

Methods and Results— Multiple human vascular specimens at distinct stages of atherosclerosis (lesion types II to V by American Heart Association classification) derived from 14 different individuals were studied for expression of these transcription factors. We observed expression of TR3, MINOR, and NOT in neointimal SMCs, whereas no expression was detected in medial SMCs. Adenovirus-mediated expression of a dominant-negative variant of TR3, which suppresses the transcriptional activity of each subfamily member, increases DNA synthesis and decreases p27^Kip1 protein expression in cultured SMCs. We generated transgenic mice that express this dominant-negative variant or full-length TR3 under control of a vascular SMC-specific promoter. Carotid artery ligation of transgenic mice that express the dominant-negative variant of TR3 in arterial SMCs, compared with lesions formed in wild-type mice, results in a 3-fold increase in neointimal formation, whereas neointimal formation is inhibited 5-fold in transgenic mice expressing full-length TR3.

Conclusions— Our results reveal that TR3 and possibly other members of this transcription factor subfamily inhibit vascular lesion formation. These transcription factors could serve as novel targets in the treatment of vascular disease.

Key Words: muscle, smooth • atherosclerosis • genes

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