PMID- 17224626
OWN - NLM
STAT- MEDLINE
DCOM- 20070718
LR  - 20211203
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 3
IP  - 3
DP  - 2007 May-Jun
TI  - Everolimus-induced mTOR inhibition selectively depletes macrophages in 
      atherosclerotic plaques by autophagy.
PG  - 241-4
AB  - Current pharmacological approaches to stabilize nonobstructive rupture-prone 
      atherosclerotic plaques have only partially reduced the incidence of acute 
      coronary syndromes and sudden death. Macrophages in these vulnerable plaques play 
      a pivotal role in plaque destabilization, whereas smooth muscle cells promote 
      plaque stability. In a recent study, we report that implantation of stents 
      eluting everolimus, a mammalian target of rapamycin (mTOR) inhibitor, in 
      atherosclerotic arteries of cholesterol-fed rabbits, led to a marked reduction in 
      macrophage content without altering the amount of smooth muscle cells. Our in 
      vitro studies showed that treatment of macrophages and smooth muscle cells with 
      everolimus induced inhibition of translation of both cell types. However, cell 
      death occurred only in macrophages and was characterized by bulk degradation of 
      long-lived proteins, processing of microtubule associated protein light chain 3 
      (LC3), and cytoplasmic vacuolization, which are all markers of autophagy. 
      Everolimus-induced autophagy was mediated by mTOR inhibition because cell 
      viability was not affected using tacrolimus, an mTOR independent 
      everolimus-analogue. These results provide proof-of-principle that macrophages in 
      the vascular wall can be selectively cleared via induction of autophagy by mTOR 
      inhibition. Therefore, stent-based delivery of an mTOR inhibitor may be a 
      promising novel strategy for treatment of vulnerable atherosclerotic plaques.
FAU - Martinet, Wim
AU  - Martinet W
AD  - Division of Pharmacology, University of Antwerp, Wilrijk, Belgium. 
      wim.martinet@ua.ac.be
FAU - Verheye, Stefan
AU  - Verheye S
FAU - De Meyer, Guido R Y
AU  - De Meyer GR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070514
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 97C5T2UQ7J (Cholesterol)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Atherosclerosis/pathology/*therapy
MH  - *Autophagy
MH  - Cholesterol/metabolism
MH  - Diet
MH  - Everolimus
MH  - Macrophages/*cytology
MH  - Myocytes, Smooth Muscle/cytology
MH  - Protein Biosynthesis/drug effects
MH  - Protein Kinases/*metabolism
MH  - Rabbits
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - Stents
MH  - TOR Serine-Threonine Kinases
EDAT- 2007/01/17 09:00
MHDA- 2007/07/19 09:00
CRDT- 2007/01/17 09:00
PHST- 2007/01/17 09:00 [pubmed]
PHST- 2007/07/19 09:00 [medline]
PHST- 2007/01/17 09:00 [entrez]
AID - 3711 [pii]
AID - 10.4161/auto.3711 [doi]
PST - ppublish
SO  - Autophagy. 2007 May-Jun;3(3):241-4. doi: 10.4161/auto.3711. Epub 2007 May 14.