PMID- 30590134
OWN - NLM
STAT- MEDLINE
DCOM- 20190506
LR  - 20211204
IS  - 1879-3649 (Electronic)
IS  - 1537-1891 (Linking)
VI  - 113
DP  - 2019 Feb
TI  - Everolimus depletes plaque macrophages, abolishes intraplaque neovascularization 
      and improves survival in mice with advanced atherosclerosis.
PG  - 70-76
LID - S1537-1891(18)30300-8 [pii]
LID - 10.1016/j.vph.2018.12.004 [doi]
AB  - BACKGROUND AND AIMS: Inhibition of the mechanistic target of rapamycin (mTOR) is 
      a promising approach to halt atherogenesis in different animal models. This study 
      evaluated whether the mTOR inhibitor everolimus can stabilize pre-existing 
      plaques, prevent cardiovascular complications and improve survival in a mouse 
      model of advanced atherosclerosis. METHODS: ApoE(-/-)Fbn1(C1039G+/-) mice 
      (n = 24) were fed a Western diet (WD) for 12 weeks. Subsequently, mice were 
      treated with everolimus (1.5 mg/kg daily) or vehicle for another 12 weeks while 
      the WD continued. RESULTS: Despite hypercholesterolemia, everolimus treatment was 
      associated with a reduction in circulating Ly6C(high) monocytes (15 vs. 28% of 
      total leukocytes, p = 0.046), a depletion of plaque macrophages (2.1 vs. 4.1%, 
      p = 0.040) and an abolishment of intraplaque neovascularization, which are all 
      indicative of a more stable plaque phenotype. Moreover, everolimus reduced 
      hypoxic brain damage and improved cardiac function, which led to increased 
      survival (100 vs. 67% of animals, p = 0.038). CONCLUSIONS: Everolimus enhances 
      features of plaque stability and counters cardiovascular complications in 
      ApoE(-/-)Fbn1(C1039G+/-) mice, even when administered at a later stage of the 
      disease.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Kurdi, Ammar
AU  - Kurdi A
AD  - Laboratory of Physiopharmacology, Department of Pharmaceutical Sciences, 
      University of Antwerp, Antwerp, Belgium.
FAU - Roth, Lynn
AU  - Roth L
AD  - Laboratory of Physiopharmacology, Department of Pharmaceutical Sciences, 
      University of Antwerp, Antwerp, Belgium.
FAU - Van der Veken, Bieke
AU  - Van der Veken B
AD  - Laboratory of Physiopharmacology, Department of Pharmaceutical Sciences, 
      University of Antwerp, Antwerp, Belgium.
FAU - Van Dam, Debby
AU  - Van Dam D
AD  - Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of 
      Antwerp, Antwerp, Belgium; Department of Neurology and Alzheimer Research Center, 
      University of Groningen and University Medical Center Groningen, Hanzeplein 1, 
      9713, GZ, Groningen, the Netherlands.
FAU - De Deyn, Peter P
AU  - De Deyn PP
AD  - Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of 
      Antwerp, Antwerp, Belgium; Department of Neurology and Alzheimer Research Center, 
      University of Groningen and University Medical Center Groningen, Hanzeplein 1, 
      9713, GZ, Groningen, the Netherlands; Department of Neurology, Memory Clinic of 
      Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Lindendreef 1, 2020 
      Antwerp, Belgium.
FAU - De Doncker, Mireille
AU  - De Doncker M
AD  - Laboratory for TDM and Toxicology, ZNA Stuivenberg, Antwerp, Belgium.
FAU - Neels, Hugo
AU  - Neels H
AD  - Laboratory for TDM and Toxicology, ZNA Stuivenberg, Antwerp, Belgium.
FAU - De Meyer, Guido R Y
AU  - De Meyer GRY
AD  - Laboratory of Physiopharmacology, Department of Pharmaceutical Sciences, 
      University of Antwerp, Antwerp, Belgium.
FAU - Martinet, Wim
AU  - Martinet W
AD  - Laboratory of Physiopharmacology, Department of Pharmaceutical Sciences, 
      University of Antwerp, Antwerp, Belgium. Electronic address: 
      wim.martinet@uantwerpen.be.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181224
PL  - United States
TA  - Vascul Pharmacol
JT  - Vascular pharmacology
JID - 101130615
RN  - 0 (Antigens, Ly)
RN  - 0 (Cardiovascular Agents)
RN  - 0 (Fbn1 protein, mouse)
RN  - 0 (Fibrillin-1)
RN  - 0 (Ly-6C antigen, mouse)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antigens, Ly/metabolism
MH  - Atherosclerosis/*drug therapy/genetics/metabolism/pathology
MH  - Brain/drug effects/pathology/physiopathology
MH  - Cardiovascular Agents/*pharmacology
MH  - Carotid Artery Diseases/*drug therapy/genetics/metabolism/pathology
MH  - Carotid Artery, Common/*drug effects/metabolism/pathology
MH  - Diet, Western
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Everolimus/*pharmacology
MH  - Female
MH  - Fibrillin-1/deficiency/genetics
MH  - Heart/drug effects/physiopathology
MH  - Hypoxia, Brain/pathology/physiopathology/prevention & control
MH  - Macrophages/*drug effects/metabolism/pathology
MH  - Mice, Knockout, ApoE
MH  - Monocytes/drug effects/metabolism
MH  - Motor Activity/drug effects
MH  - Myocardial Contraction/drug effects
MH  - *Neovascularization, Pathologic
MH  - *Plaque, Atherosclerotic
MH  - Protein Kinase Inhibitors/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
OTO - NOTNLM
OT  - *Advanced atherosclerosis
OT  - *Brain hypoxia
OT  - *Everolimus
OT  - *Intraplaque neovascularization
OT  - *mTOR inhibition
EDAT- 2018/12/28 06:00
MHDA- 2019/05/07 06:00
CRDT- 2018/12/28 06:00
PHST- 2018/08/14 00:00 [received]
PHST- 2018/10/31 00:00 [revised]
PHST- 2018/12/23 00:00 [accepted]
PHST- 2018/12/28 06:00 [pubmed]
PHST- 2019/05/07 06:00 [medline]
PHST- 2018/12/28 06:00 [entrez]
AID - S1537-1891(18)30300-8 [pii]
AID - 10.1016/j.vph.2018.12.004 [doi]
PST - ppublish
SO  - Vascul Pharmacol. 2019 Feb;113:70-76. doi: 10.1016/j.vph.2018.12.004. Epub 2018 
      Dec 24.