PMID- 23449430
OWN - NLM
STAT- MEDLINE
DCOM- 20130415
LR  - 20220112
IS  - 1558-3597 (Electronic)
IS  - 0735-1097 (Print)
IS  - 0735-1097 (Linking)
VI  - 61
IP  - 9
DP  - 2013 Mar 5
TI  - 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.
PG  - 971-80
LID - S0735-1097(13)00019-3 [pii]
LID - 10.1016/j.jacc.2012.12.018 [doi]
AB  - 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.
CI  - Copyright (c) 2013 American College of Cardiology Foundation. Published by Elsevier 
      Inc. All rights reserved.
FAU - Habib, Anwer
AU  - Habib A
AD  - Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA 
      30322, USA.
FAU - Karmali, Vinit
AU  - Karmali V
FAU - Polavarapu, Rohini
AU  - Polavarapu R
FAU - Akahori, Hirokuni
AU  - Akahori H
FAU - Nakano, Masataka
AU  - Nakano M
FAU - Yazdani, Saami
AU  - Yazdani S
FAU - Otsuka, Fumiyuki
AU  - Otsuka F
FAU - Pachura, Kim
AU  - Pachura K
FAU - Davis, Talina
AU  - Davis T
FAU - Narula, Jagat
AU  - Narula J
FAU - Kolodgie, Frank D
AU  - Kolodgie FD
FAU - Virmani, Renu
AU  - Virmani R
FAU - Finn, Aloke V
AU  - Finn AV
LA  - eng
GR  - R01 HL096970/HL/NHLBI NIH HHS/United States
GR  - R01 HL096970-01A/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Am Coll Cardiol
JT  - Journal of the American College of Cardiology
JID - 8301365
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - H4GXR80IZE (zotarolimus)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Aorta/cytology
MH  - Apoptosis
MH  - Cell Proliferation/*drug effects
MH  - Cells, Cultured
MH  - Drug Interactions
MH  - *Drug-Eluting Stents
MH  - Endothelial Cells/cytology/*drug effects
MH  - Endothelium, Vascular/cytology
MH  - Humans
MH  - Iliac Artery
MH  - Metformin/administration & dosage/*adverse effects
MH  - Microscopy, Electron, Scanning
MH  - Rabbits
MH  - Ribosomal Protein S6 Kinases/antagonists & inhibitors/*physiology
MH  - Sirolimus/analogs & derivatives/*antagonists & inhibitors/pharmacology
PMC - PMC3942872
MID - NIHMS552043
EDAT- 2013/03/02 06:00
MHDA- 2013/04/16 06:00
PMCR- 2014/03/05
CRDT- 2013/03/02 06:00
PHST- 2012/10/13 00:00 [received]
PHST- 2012/12/07 00:00 [revised]
PHST- 2012/12/11 00:00 [accepted]
PHST- 2013/03/02 06:00 [entrez]
PHST- 2013/03/02 06:00 [pubmed]
PHST- 2013/04/16 06:00 [medline]
PHST- 2014/03/05 00:00 [pmc-release]
AID - S0735-1097(13)00019-3 [pii]
AID - 10.1016/j.jacc.2012.12.018 [doi]
PST - ppublish
SO  - J Am Coll Cardiol. 2013 Mar 5;61(9):971-80. doi: 10.1016/j.jacc.2012.12.018.