Differential Healing After Sirolimus, Paclitaxel, and Bare Metal Stent Placement in Combination With Peroxisome Proliferator-Activator Receptor gamma Agonists Requirement for mTOR/Akt2 in PPAR gamma Activation

• Type of Material: Article
• Authors: Aloke Finn, Emory University; Michael John, Emory University; Gaku Nakazawa, CVPath Institute, Inc.; Rohini Polavarapu, Emory University; Vinit Karmali, Emory University; Xin Xu, CVPath Institute, Inc.; Qi Cheng, CVPath Institute, Inc.; Talina Davis, Emory University; Chitra Raghunathan, Emory University; Eduardo Acampado, CVPath Institute, Inc.; Tucker Ezell, Emory University; Scott Lajoie, Emory University; Michael Eppihimer, Boston Scientific; Frank D Kolodgie, CVPath Institute, Inc.; Renu Virmani, CVPath Institute, Inc.; Herman Kalman Gold, Massachusetts General Hospital
• Language: English
• Date: 2009-11-06
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCRESAHA.109.200519
• Title of Journal or Parent Work: Circulation Research
• ISSN: 0009-7330
• Volume: 105
• Issue: 10
• Start Page: 1003
• End Page: 1012
• Grant/Funding Information: This study was supported in part by a grant from Boston Scientific.; AVF is supported by the Carlyle Fraser Heart Center at Emory.; RV has received company-sponsored research support from Medtronic AVE, Abbott Vascular, W.L. Gore, Atrium Medical Corporation, Boston Scientific, NDC Cordis Corporation, Novartis, Orbus Medical Technologies, Biotronik, BioSensors, Alchimer, and Terumo, and is a consultant for Medtronic AVE, Guidant, Abbott Laboratories, W.L. Gore, Terumo, and Volcano Therapeutics Inc.; AVF has a sponsored research agreement with Boston Scientific which supported part of this work.
• Keywords: MAMMALIAN TARGET; EXPRESSION; MTOR; endothelium; thrombosis; Cardiac & Cardiovascular Systems; GROWTH; Cardiovascular System & Cardiology; DRUG-ELUTING STENTS; Science & Technology; PROTEIN-SYNTHESIS; stents; ENDOTHELIAL-CELLS; ROSIGLITAZONE; Hematology; Life Sciences & Biomedicine; Peripheral Vascular Disease; pharmacology; PGC-1-ALPHA; RAPAMYCIN
• Research Categories: Health Sciences, General; Health Sciences, Medicine and Surgery

Abstract

Rationale: Sirolimus-eluting coronary stents (SESs) and paclitaxel-eluting coronary stents (PESs) are used to reduce restenosis but have different sites of action. The molecular targets of sirolimus overlap with those of the peroxisome proliferator-activated receptor (PPAR)γ agonist rosiglitazone (RSG) but the consequence of this interaction on endothelialization is unknown. Objective: Using the New Zealand white rabbit iliac model of stenting, we examined the effects of RSG on SESs, PESs, and bare metal stents endothelialization. Methods and Results: Animals receiving SESs, PESs, or bare metal stents and either RSG (3 mg/kg per day) or placebo were euthanized at 28 days, and arteries were evaluated by scanning electron microscopy. Fourteen-day organ culture and Western blotting of iliac arteries and tissue culture experiments were conducted. Endothelialization was significantly reduced by RSG in SESs but not in PESs or bare metal stents. Organ culture revealed reduced vascular endothelial growth factor in SESs receiving RSG compared to RSG animals receiving bare metal stent or PESs. Quantitative polymerase chain reaction in human aortic endothelial cells (HAECs) revealed that sirolimus (but not paclitaxel) inhibited RSG-induced vascular endothelial growth factor transcription. Western blotting demonstrated that inhibition of molecular signaling in SES+RSG-treated arteries was similar to findings in HAECs treated with RSG and small interfering RNA to PPARγ, suggesting that sirolimus inhibits PPARγ. Transfection of HAECs with mTOR (mammalian target of rapamycin) short hairpin RNA and with Akt2 small interfering RNA significantly inhibited RSG-mediated transcriptional upregulation of heme oxygenase-1, a PPARγ target gene. Chromatin immunoprecipitation assay demonstrated sirolimus interferes with binding of PPARγ to its response elements in heme oxygenase-1 promoter. Conclusions: mTOR/Akt2 is required for optimal PPARγ activation. Patients who receive SESs during concomitant RSG treatment may be at risk for delayed stent healing.