title: 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.
abstract: OBJECTIVE
  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.
authors: Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Anwer
authors: A
authors: Habib
authors: Vinit
authors: V
authors: Karmali
authors: Rohini
authors: R
authors: Polavarapu
authors: Hirokuni
authors: H
authors: Akahori
authors: Masataka
authors: M
authors: Nakano
authors: Saami
authors: S
authors: Yazdani
authors: Fumiyuki
authors: F
authors: Otsuka
authors: Kim
authors: K
authors: Pachura
authors: Talina
authors: T
authors: Davis
authors: Jagat
authors: J
authors: Narula
authors: Frank D
authors: FD
authors: Kolodgie
authors: Renu
authors: R
authors: Virmani
authors: Aloke V
authors: AV
authors: Finn
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004347:Drug Interactions; D054855:Drug-Eluting Stents; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007083:Iliac Artery; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects*; D008855:Microscopy, Electron, Scanning; D011817:Rabbits; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D008687:Metformin; D019893:Ribosomal Protein S6 Kinases; C489443:zotarolimus; D020123:Sirolimus