PMID- 22785139
OWN - NLM
STAT- MEDLINE
DCOM- 20130517
LR  - 20190608
IS  - 1880-3873 (Electronic)
IS  - 1340-3478 (Linking)
VI  - 19
IP  - 11
DP  - 2012
TI  - Dietary cholesterol oxidation products accelerate plaque destabilization and 
      rupture associated with monocyte infiltration/activation via the MCP-1-CCR2 
      pathway in mouse brachiocephalic arteries: therapeutic effects of ezetimibe.
PG  - 986-98
AB  - AIM: No prior studies have investigated the effects of dietary cholesterol 
      oxidation products (oxysterols) on atherosclerotic plaque destabilization and 
      rupture. We used an atherosclerotic mouse model with histological features 
      similar to those seen in ruptured human plaques to test the hypothesis that (1) 
      dietary oxysterols accelerate plaque destabilization and rupture and (2) a NPC1L1 
      inhibitor, ezetimibe, has therapeutic effects on these processes. METHODS AND 
      RESULTS: Advanced atherosclerotic plaques were examined in innominate arteries of 
      ApoE(-/-) mice that were fed either a regular high-fat diet (HFD) or HFD 
      containing oxysterols (oxysterol-HFD; 6.8% of added cholesterol was oxidized) and 
      infused with angiotensin II. Compared with HFD, oxysterol-HFD did not affect 
      plasma lipid levels but did accelerate plaque destabilization and rupture, which 
      was associated with increased monocyte infiltration/activation, monocyte 
      chemoattractant protein-1 (MCP-1) expression, and matrix metalloproteinase (MMP) 
      activity. Dietary oxysterol-induced plaque destabilization and rupture were 
      blunted in ApoE(-/-) CCR2(-/-) mice. Oral treatment with ezetimibe, significantly 
      decreased plasma lipid levels and prevented the acceleration of plaque 
      destabilization and rupture induced by dietary oxysterol. These data indicate a 
      primary role for monocyte-mediated inflammation via the MCP-1-CCR2 pathway and 
      the resultant increase in MMP activity in plaque destabilization and rupture 
      induced by dietary oxysterols in ApoE(-/-) mice. These data also provide a 
      mechanism by which dietary oxysterols are connected with the pathogenesis of 
      plaque destabilization and rupture. CONCLUSIONS: These data suggest that 
      inhibition of the absorption of oxysterols by ezetimibe may be useful for the 
      treatment of high-risk patients with high oxysterol intake.
FAU - Sato, Kei
AU  - Sato K
AD  - Department of Cardiovascular Medicine, Graduate School of Medical Sciences, 
      Kyushu University, Fukuoka, Japan.
FAU - Nakano, Kaku
AU  - Nakano K
FAU - Katsuki, Shunsuke
AU  - Katsuki S
FAU - Matoba, Tetsuya
AU  - Matoba T
FAU - Osada, Kyoichi
AU  - Osada K
FAU - Sawamura, Tatsuya
AU  - Sawamura T
FAU - Sunagawa, Kenji
AU  - Sunagawa K
FAU - Egashira, Kensuke
AU  - Egashira K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120711
PL  - Japan
TA  - J Atheroscler Thromb
JT  - Journal of atherosclerosis and thrombosis
JID - 9506298
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Azetidines)
RN  - 0 (Ccr2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Cholesterol, Dietary)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Sterols)
RN  - EOR26LQQ24 (Ezetimibe)
SB  - IM
MH  - Animals
MH  - Anticholesteremic Agents/*therapeutic use
MH  - Apolipoproteins E/genetics
MH  - Azetidines/*therapeutic use
MH  - Brachiocephalic Trunk/*metabolism
MH  - Chemokine CCL2/*metabolism
MH  - Cholesterol, Dietary/*metabolism
MH  - Ezetimibe
MH  - Flow Cytometry
MH  - Gas Chromatography-Mass Spectrometry
MH  - Immunohistochemistry
MH  - Liver/metabolism
MH  - Lymphocyte Activation
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Monocytes/cytology
MH  - Oxidation-Reduction
MH  - Oxidative Stress
MH  - Plaque, Atherosclerotic/*metabolism
MH  - Receptors, CCR2/*metabolism
MH  - Sterols/blood/metabolism
EDAT- 2012/07/13 06:00
MHDA- 2013/05/18 06:00
CRDT- 2012/07/13 06:00
PHST- 2012/07/13 06:00 [entrez]
PHST- 2012/07/13 06:00 [pubmed]
PHST- 2013/05/18 06:00 [medline]
AID - DN/JST.JSTAGE/jat/13391 [pii]
AID - 10.5551/jat.13391 [doi]
PST - ppublish
SO  - J Atheroscler Thromb. 2012;19(11):986-98. doi: 10.5551/jat.13391. Epub 2012 Jul 
      11.