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

Kei Sato, Kaku Nakano, Shunsuke Katsuki, Tetsuya Matoba, Kyoichi Osada, Tatsuya Sawamura, Kenji Sunagawa, Kensuke Egashira

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)986-998
Number of pages13
JournalJournal of atherosclerosis and thrombosis
Volume19
Issue number11
DOIs
Publication statusPublished - Dec 13 2012

Fingerprint

Dietary Cholesterol
Chemokine CCL2
Therapeutic Uses
Nutrition
Infiltration
Rupture
Monocytes
Arteries
Chemical activation
Fats
Apolipoproteins E
Oxidation
High Fat Diet
Matrix Metalloproteinases
Lipids
Plasmas
Atherosclerotic Plaques
Angiotensin II
Cholesterol
Ezetimibe

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Cardiology and Cardiovascular Medicine
  • Biochemistry, medical

Cite this

@article{47fa1e09112441a2bad7340ff3b724ff,
title = "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",
abstract = "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.",
author = "Kei Sato and Kaku Nakano and Shunsuke Katsuki and Tetsuya Matoba and Kyoichi Osada and Tatsuya Sawamura and Kenji Sunagawa and Kensuke Egashira",
year = "2012",
month = "12",
day = "13",
doi = "10.5551/jat.13391",
language = "English",
volume = "19",
pages = "986--998",
journal = "Journal of Atherosclerosis and Thrombosis",
issn = "1340-3478",
publisher = "Japan Atherosclerosis Society",
number = "11",

}

TY - JOUR

T1 - Dietary cholesterol oxidation products accelerate plaque destabilization and rupture associated with monocyte infiltration/activation via the MCP-1-CCR2 pathway in mouse brachiocephalic arteries

T2 - Therapeutic effects of ezetimibe

AU - Sato, Kei

AU - Nakano, Kaku

AU - Katsuki, Shunsuke

AU - Matoba, Tetsuya

AU - Osada, Kyoichi

AU - Sawamura, Tatsuya

AU - Sunagawa, Kenji

AU - Egashira, Kensuke

PY - 2012/12/13

Y1 - 2012/12/13

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84870749692&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870749692&partnerID=8YFLogxK

U2 - 10.5551/jat.13391

DO - 10.5551/jat.13391

M3 - Article

C2 - 22785139

AN - SCOPUS:84870749692

VL - 19

SP - 986

EP - 998

JO - Journal of Atherosclerosis and Thrombosis

JF - Journal of Atherosclerosis and Thrombosis

SN - 1340-3478

IS - 11

ER -