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Activation of nuclear receptor Nur77 by 6-mercaptopurine protects against neointima formation

Author: Pires, N.M.M. · Pols, T.W.H. · Vries, M.R. de · Tiel, C.M.van · Bonta, P.I. · Vos, M. · Arkenbout, E.K. · Pannekoek, H. · Jukema, J.W. · Quax, P.H.A. · Vries, C.J.M. de
Type:article
Date:2007
Institution: TNO Kwaliteit van Leven
Source:Circulation, 4, 115, 493-500
Identifier: 239808
doi: doi:10.1161/CIRCULATIONAHA.106.626838
Keywords: Biology · Biomedical Research · Muscle, smooth · Receptors, cytoplasmic and nuclear · Restenosis · Stents · Transcription factors · cyclin dependent kinase inhibitor 1B · cycline · mercaptopurine · messenger RNA · nuclear receptor Nur77 · polycaprolactone · small interfering RNA · staurosporine · thymidine · tritium · animal experiment · animal model · animal tissue · antiangiogenic activity · antigen expression · apoptosis · artery intima proliferation · article · blood vessel injury · blood vessel wall · cell culture · cell cycle arrest · cell proliferation · controlled study · DNA synthesis · drug delivery system · drug dose comparison · drug effect · elution · experimental model · femoral artery · gene overexpression · human · human cell · hypothesis · in-stent restenosis · inflammation · intima · local therapy · male · mouse · nonhuman · observation · priority journal · protein expression · receptor down regulation · receptor upregulation · smooth muscle fiber · sustained drug release · transgenic mouse · vascular smooth muscle · wild type · 6-Mercaptopurine · Animals · Antimetabolites, Antineoplastic · Apoptosis · Cell Division · Cells, Cultured · Coronary Restenosis · Disease Models, Animal · DNA-Binding Proteins · Drug Implants · Femoral Artery · Humans · Male · Mice · Mice, Inbred Strains · Mice, Transgenic · Muscle, Smooth, Vascular · Receptors, Cytoplasmic and Nuclear · Receptors, Steroid · RNA, Messenger · RNA, Small Interfering · Transcription Factors · Tunica Intima · Umbilical Arteries

Abstract

BACKGROUND - Restenosis is a common complication after percutaneous coronary interventions and is characterized by excessive proliferation of vascular smooth muscle cells (SMCs). We have shown that the nuclear receptor Nur77 protects against SMC-rich lesion formation, and it has been demonstrated that 6-mercaptopurine (6-MP) enhances Nur77 activity. We hypothesized that 6-MP inhibits neointima formation through activation of Nur77. METHODS AND RESULTS - It is demonstrated that 6-MP increases Nur77 activity in cultured SMCs, which results in reduced [H]thymidine incorporation, whereas Nur77 small interfering RNA knockdown partially restores DNA synthesis. Furthermore, we studied the effect of 6-MP in a murine model of cuff-induced neointima formation. Nur77 mRNA is upregulated in cuffed arteries, with optimal expression after 6 hours and elevated expression up to 7 days after vascular injury. Local perivascular delivery of 6-MP with a drug-eluting cuff significantly inhibits neointima formation in wild-type mice. Locally applied 6-MP does not affect inflammatory responses or apoptosis but inhibits expression of proliferating cell nuclear antigen and enhances protein levels of the cell-cycle inhibitor p27 in the vessel wall. An even stronger inhibition of neointima formation in response to local 6-MP delivery was observed in transgenic mice that overexpressed Nur77. In contrast, 6-MP does not alter lesion formation in transgenic mice that overexpress a dominant-negative variant of Nur77 in arterial SMCs, which provides evidence for the involvement of Nur77-like factors. CONCLUSIONS - Enhancement of the activity of Nur77 by 6-MP protects against excessive SMC proliferation and SMC-rich neointima formation. We propose that activation of the nuclear receptor Nur77 is a rational approach to treating in-stent restenosis. © 2007 American Heart Association, Inc. Chemicals / CAS: mercaptopurine, 31441-78-8, 50-44-2, 6112-76-1; polycaprolactone, 24980-41-4, 25248-42-4; staurosporine, 62996-74-1; thymidine, 50-89-5; tritium, 10028-17-8; 6-Mercaptopurine, 50-44-2; Antimetabolites, Antineoplastic; DNA-Binding Proteins; Drug Implants; orphan nuclear receptor NGFI-B, 121479-42-3; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; RNA, Messenger; RNA, Small Interfering; Transcription Factors