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

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-3] 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(Kip1) 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.