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