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

Sato, Katsuaki; Nakano, K.; Katsuki, S.; Matoba, Tetsuya; Osada, Kyoichi; Sawamura, Tatsuya; Sunagawa, Kenji; Egashira, Kensuke

doi:10.5551/jat.13391

Cited by 47 publications

(32 citation statements)

References 34 publications

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“…Several oxysterols have been identified in humans and atherosclerotic animal models. 9,12 Although there are several nonhuman studies suggesting a detrimental role of 7-KC 35 and 27-hydroxycholesterol 36,37 on endothelial function, this study shows the association of oxysterols with endothelial dysfunction in humans. Treatment with ezetimibe was associated with the inhibition of sterol absorption and decreases of both enzymatic (intrinsic) and nonenzymatic oxysterols through the inhibition of sterol absorption.…”

Section: Cholesterol Absorption and Lipid Oxidationmentioning

confidence: 97%

“…11 We have previously shown that dietary oxysterols accelerate atherosclerotic plaque destabilization in hypercholesterolemic mice, and this acceleration is ameliorated by ezetimibe monotherapy, which is associated with decreases in serum LDL-C, oxidized LDL, and oxysterol levels. 12 These findings led us to hypothesize that ezetimibe may confer clinical benefits when used in combination with statins by acting via different mechanisms than statins.…”

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confidence: 99%

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Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting

Takase

Matoba

Nakashiro

et al. 2017

ATVB

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Objectives-We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting. Approach and Results-We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6-to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol-matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels. Conclusions-The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction afterCoronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional prognoses, ameliorating endothelial dysfunction in stented coronary arteries, and was associated with larger decreases in oxysterol levels. From the Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan (S.T., T.M., S.N., T.H., K. Egashira, K. Sunagawa); Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan (S.T., T.M., S.N., Y.M., S.I., K.O., T.H., S.K., M.T., K. Sunagawa); Japanese Red Cross Fukuoka Hospital, Japan (N.S.); St. Mary's Hospital, Kurume, Japan (K. Eshima); Japan Community Health Care Organization, Kyushu Hospital, Fukuoka, Japan (K.M.); Harasanshin Hospital, Fukuoka, Japan (M.Y.); Hamanomachi Hospital, Fukuoka, Japan (M.U.); Saga-ken Medical Centre Koseikan, Saga, Japan (K. Sadamatsu); National Hospital Organization Kyushu Medical Centre, Fukuoka, Japan (S.S.); Saiseikai Futsukaichi Hospital, Chikushino, Japan (T.K.); Saiseikai Fukuoka General Hospital, Japan; Fukuoka City Hospital, Japan (K.H.); Graduate School of ...

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Section: Cholesterol Absorption and Lipid Oxidationmentioning

confidence: 97%

mentioning

confidence: 99%

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting

Takase

Matoba

Nakashiro

et al. 2017

ATVB

Self Cite

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“…[6][7][8][9][10]23,[28][29][30][31][32] For example, they were distributed in endothelial cells after injection into ischemic muscles, whereas intratracheal administration resulted in delivery to alveolar macrophages and small pulmonary arteries. When administered intravenously, nanoparticles were taken up by peripheral monocytes and neutrophils.…”

Section: Discussionmentioning

confidence: 99%

“…The number of buried fibrous caps in the brachiocephalic arteries was determined as a surrogate marker of plaque rupture. 9,21,23 Daily oral administration of 1 mg/kg pioglitazone did not significantly affect the number of buried fibrous caps, thickness of fibrous caps, or the plaque area ( Figure 3A). Orally administered pioglitazone did not decrease macrophage accumulation as determined by Mac-3 staining.…”

Section: Intravenous Administration Of Pioglitazonenps Skews the Perimentioning

confidence: 99%

Pioglitazone-Incorporated Nanoparticles Prevent Plaque Destabilization and Rupture by Regulating Monocyte/Macrophage Differentiation in ApoE ^−/− Mice

Nakashiro

Matoba

Umezu

et al. 2016

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Objective-Inflammatory monocytes/macrophages produce various proteinases, including matrix metalloproteinases, and degradation of the extracellular matrix by these activated proteinases weakens the mechanical strength of atherosclerotic plaques, which results in a rupture of the plaque. Peroxisome proliferator-activated receptor-γ induces a polarity shift of monocytes/macrophages toward less inflammatory phenotypes and has the potential to prevent atherosclerotic plaque ruptures. Therefore, we hypothesized that nanoparticle-mediated targeted delivery of the peroxisome proliferatoractivated receptor-γ agonist pioglitazone into circulating monocytes could effectively inhibit plaque ruptures in a mouse model. Approach and Results-We prepared bioabsorbable poly(lactic-co-glycolic-acid) nanoparticles containing pioglitazone (pioglitazone-NPs). Intravenously administered poly(lactic-co-glycolic-acid) nanoparticles incorporated with fluorescein isothiocyanate were found in circulating monocytes and aortic macrophages by flow cytometric analysis. Weekly intravenous administration of pioglitazone-NPs (7 mg/kg per week) for 4 weeks decreased buried fibrous caps, a surrogate marker of plaque rupture, in the brachiocephalic arteries of ApoE −/− mice fed a high-fat diet and infused with angiotensin II. In contrast, administration of control-NPs or an equivalent dose of oral pioglitazone treatment produced no effects. Pioglitazone-NPs inhibited the activity of matrix metalloproteinases and cathepsins in the brachiocephalic arteries. Pioglitazone-NPs regulated inflammatory cytokine expression and also suppressed the expression of extracellular matrix metalloproteinase inducer in bone marrow-derived macrophages. Conclusions-Nanoparticle-mediated delivery of pioglitazone inhibited macrophage activation and atherosclerotic plaque ruptures in hyperlipidemic ApoE −/− mice. These results demonstrate a promising strategy with a favorable safety profile to prevent atherosclerotic plaque ruptures.

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“…Clinical and genetic studies have revealed that MMP-2 and MMP-9 are involved in the onset of acute coronary syndrome (ACS) [8-10]. In addition, excessive levels of angiotensin II (Ang II), the major stress hormone in the rennin-angiotensin system (RAS), have been confirmed to accelerate the progression of atherosclerotic plaques toward instability via MMPs induction [11, 12]. These actions are mainly mediated through Ang II type 1 receptor (AT1R) [11, 13, 14] and its downstream signaling molecules, including nuclear factor-kappa B (NF-κB), liver X receptor α (LXRα), Toll-like receptors (TLRs) and peroxisome proliferators–activated receptor γ (PPARγ) [15-17].…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II Suppresses Rev-erbα Expression in THP-1 Macrophages via the Ang II Type 1 Receptor/Liver X Receptor α Pathway

Wang

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Angiotensin II (Ang II) regulates the expression of some core clock genes; excess Ang II leads to atherosclerosis advancement. Macrophage Rev-erbα mediates clockwork and inflammation, and plays a role in atherosclerotic lesion progression. However, the role of Ang II in regulating Rev-erbα expression in macrophages remains unclarified. Methods: We induced THP-1 macrophages by phorbol 12-myristate 13-acetate and investigated the effect of Ang II on Rev-erbα expression via real-time polymerase chain reaction, western blotting and small interfering RNA (siRNA) techniques. The cytotoxicity of the Rev-erbα agonist SR9009 was analyzed using a (3-[4,5-dimethylthiazol-2-yl])-2,5- diphenyltetrazolium bromide assay. Results: Ang II suppressed Rev-erbα mRNA and protein expression in THP-1 macrophages in a dose and time dependent manner. This effect was mediated via Ang II type 1 receptor (AT1R), and not Ang II type 2 receptor or peroxisome proliferator-activated receptor γ (PPARγ). Consistent with Rev-erbα expression regulated by Ang II, the liver X receptor α (LXRα) protein expression was downregulated in a time-dependent manner after Ang II treatment. The activation or silence of LXRα significantly increased or decreased Rev-erbα expression regulated by Ang II, respectively. This suggests that LXRα is involved in the effect of Ang II on Rev-erbα expression. MMP-9 mRNA expressions were significantly suppressed by SR9009 in THP-1 and RAW264.7 macrophages; moreover, SR9009-treatment significantly reduced Ang II–induced MMP-9 protein expressions in two types of macrophages. Conclusion: Ang II downregulates Rev-erbα expression in THP-1 macrophages via the AT1R/LXRα pathway.

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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

Cited by 47 publications

References 34 publications

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting

Pioglitazone-Incorporated Nanoparticles Prevent Plaque Destabilization and Rupture by Regulating Monocyte/Macrophage Differentiation in ApoE ^−/− Mice

Angiotensin II Suppresses Rev-erbα Expression in THP-1 Macrophages via the Ang II Type 1 Receptor/Liver X Receptor α Pathway

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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

Cited by 47 publications

References 34 publications

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting

Pioglitazone-Incorporated Nanoparticles Prevent Plaque Destabilization and Rupture by Regulating Monocyte/Macrophage Differentiation in ApoE −/− Mice

Angiotensin II Suppresses Rev-erbα Expression in THP-1 Macrophages via the Ang II Type 1 Receptor/Liver X Receptor α Pathway

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Pioglitazone-Incorporated Nanoparticles Prevent Plaque Destabilization and Rupture by Regulating Monocyte/Macrophage Differentiation in ApoE ^−/− Mice