Document Detail

Metformin impairs vascular endothelial recovery after stent placement in the setting of locally eluted mammalian target of rapamycin inhibitors via S6 kinase-dependent inhibition of cell proliferation.
MedLine Citation:
PMID:  23449430     Owner:  NLM     Status:  MEDLINE    
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.
Anwer Habib; Vinit Karmali; Rohini Polavarapu; Hirokuni Akahori; Masataka Nakano; Saami Yazdani; Fumiyuki Otsuka; Kim Pachura; Talina Davis; Jagat Narula; Frank D Kolodgie; Renu Virmani; Aloke V Finn
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  61     ISSN:  1558-3597     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-01     Completed Date:  2013-04-15     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  971-80     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Administration, Oral
Aorta / cytology
Cell Proliferation / drug effects*
Cells, Cultured
Drug Interactions
Drug-Eluting Stents*
Endothelial Cells / cytology,  drug effects*
Endothelium, Vascular / cytology
Iliac Artery
Metformin / administration & dosage,  adverse effects*
Microscopy, Electron, Scanning
Ribosomal Protein S6 Kinases / antagonists & inhibitors,  physiology*
Sirolimus / analogs & derivatives,  antagonists & inhibitors*,  pharmacology
Grant Support
Reg. No./Substance:
0/zotarolimus; 9100L32L2N/Metformin; EC Protein S6 Kinases; W36ZG6FT64/Sirolimus

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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