Author + information
- Received October 13, 2012
- Revision received December 7, 2012
- Accepted December 11, 2012
- Published online March 5, 2013.
- Anwer Habib, MD*,
- Vinit Karmali, MA*,
- Rohini Polavarapu, BA*,
- Hirokuni Akahori, MD, PhD*,
- Masataka Nakano, MD†,
- Saami Yazdani, PhD†,
- Fumiyuki Otsuka, MD†,
- Kim Pachura, BS*,
- Talina Davis*,
- Jagat Narula, MD, PhD‡,
- Frank D. Kolodgie, PhD†,
- Renu Virmani, MD† and
- Aloke V. Finn, MD*,* ()
- ↵*Reprint requests and correspondence:
Dr. Aloke Virmani Finn, Department of Internal Medicine, Emory University, 101 Woodruff Circle, WMB 319B, Atlanta, Georgia 30322
Objectives This study sought to examine the effect of oral metformin (Mf) therapy on endothelialization in the setting of drug-eluting stents (DES).
Background Mf is a commonly used therapy in diabetic patients receiving DES. Mf and locally eluted mammalian target of rapamycin (mTOR) inhibitors used in DES have convergent molecular signaling; however, the impact of this drug interaction on stent endothelialization is unknown.
Methods We examined human endothelial aortic cells (HAECs) and a rabbit model of stenting to determine points on molecular convergence between these 2 agents and their impact on stent endothelialization.
Results Western blotting of HAECs treated with Mf and the mTOR inhibitor sirolimus and 14-day rabbit iliacs treated with the combination of zotarolimus-eluting stents (ZES) and oral Mf demonstrated greater inhibition of S6 kinase (S6K), a downstream effector of mTOR complex 1, than either treatment alone. HAEC proliferation was significantly inhibited by Mf or sirolimus treatments alone and further reduced when they were combined. Knockdown of S6K via short interfering RNA in HAECs impaired cell proliferation via a cyclin D1–dependent mechanism, whereas its overexpression rescued the antiproliferative effects of both agents. Last, endothelialization and endothelial cell proliferation at 14 days were assessed in rabbits receiving ZES or bare-metal stents and Mf or placebo by scanning electron microscopy and bromodeoxyuridine/CD31 labeling, respectively. Both endpoints were inhibited by ZES treatment alone and were further reduced by the combination of Mf and ZES.
Conclusions Significant convergence of signaling occurs between Mf and locally delivered mTOR inhibitors at S6K. This further impairs endothelial recovery/proliferation via an S6K-dependent mechanism. Patients receiving Mf in combination with stents that elute mTOR inhibitors are potentially at increased risk of delayed endothelial healing and stent thrombosis.
This study was supported by the Carlyle Fraser Heart Center, CVPath Inc., American Heart Association and US NIH grant RO1 HL096970-01A. CVPath Institute has research grants from Medtronic CardioVascular, Abbott Vascular, Terumo Corporation, Atrium Medical, Boston Scientific, Cordis/Johnson & Johnson, OrbusNeich Medical, and Biosensors International.
Dr. Narula is a consultant for N-terminus Research Laboratory, en-N-Tech and St. Jude Medical, Inc. and is on the advisory board for Philips Healthcare, GE HealthCare and Atkins Nutritional Inc. Dr. Virmani is a consultant for Medtronic CardioVascular, Abbott Vascular, Terumo Corporation, Atrium Medical, W.L. Gore, and Lutonix. Dr. Finn has sponsored research agreements with Medtronic CardioVascular and Boston Scientific and is on the advisory board of Medtronic CardioVascular. Dr. Habib is supported by an American Heart Association Postdoctoral Fellowship grant (Greater Southeast Affiliate). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Neil Kleinman, MD, has served as Guest Editor for this paper.
- Received October 13, 2012.
- Revision received December 7, 2012.
- Accepted December 11, 2012.
- American College of Cardiology Foundation