Abstract 469: Activation of Nuclear Orphan Receptor Nur77 by 6-Mercaptopurine Protects Against Neointima Formation
Introduction: The nuclear orphan receptor Nur77 is known to protect against smooth muscle cell (SMC)-rich neointimal lesion formation and it has been demonstrated that 6-mercaptopurine (6-MP) enhances the activity of Nur77.
Hypothesis: We hypothesized that 6-MP inhibits neointima formation through activation of Nur77.
Methods and Results: We demonstrate that 6-MP increases Nur77 activity in cultured human SMCs, and reduces [3H]thymidine incorporation, whereas Nur77 siRNA-knockdown partially restores 6-MP inhibited DNA synthesis. Furthermore, the effect of 6-MP on Nur77 was studied in a murine model of cuff-induced neointima formation. Nur77 mRNA levels are upregulated in neointimal lesions, with optimal expression 6 hours after vascular injury and Nur77 mRNA levels remain elevated up to 7 days. Local perivascular delivery of 6-MP using a drug-eluting cuff, a model mimicking drug-eluting stents, significantly inhibits neointima formation in wild-type mice. An even stronger inhibition of neointima formation in response to local 6-MP delivery was observed in transgenic mice overexpressing Nur77. In contrast, 6-MP does not affect neointima formation in transgenic mice overexpressing a dominant-negative variant of Nur77 in arterial SMCs, providing further evidence for the involvement of the nuclear receptor Nur77.
Conclusions: Enhancing 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 treat (in-stent) restenosis.