Activation of nuclear receptor Nur77 by 6-mercaptopurine protects against neointima formation
article
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
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
Topics
Biomedical ResearchMuscle, smoothReceptors, cytoplasmic and nuclearRestenosisStentsTranscription factorsCyclin dependent kinase inhibitor 1BCyclineMercaptopurineMessenger RNANuclear receptor Nur77PolycaprolactoneSmall interfering RNAStaurosporineThymidineTritiumAnimal experimentAnimal modelAnimal tissueAntiangiogenic activityAntigen expressionApoptosisArtery intima proliferationBlood vessel injuryBlood vessel wallCell cultureCell cycle arrestCell proliferationControlled studyDNA synthesisDrug delivery systemDrug dose comparisonDrug effectElutionExperimental modelFemoral arteryGene overexpressionHumanHuman cellHypothesisIn-stent restenosisInflammationIntimaLocal therapyMaleMouseNonhumanObservationPriority journalProtein expressionReceptor down regulationReceptor upregulationSmooth muscle fiberSustained drug releaseTransgenic mouseVascular smooth muscleWild type6-MercaptopurineAnimalsAntimetabolites, AntineoplasticApoptosisCell DivisionCells, CulturedCoronary RestenosisDisease Models, AnimalDNA-Binding ProteinsDrug ImplantsFemoral ArteryHumansMaleMiceMice, Inbred StrainsMice, TransgenicMuscle, Smooth, VascularReceptors, Cytoplasmic and NuclearReceptors, SteroidRNA, MessengerRNA, Small InterferingTranscription FactorsTunica IntimaUmbilical Arteries
TNO Identifier
239808
ISSN
00097322
Source
Circulation, 115(4), pp. 493-500.
Pages
493-500