Oxidized LDL in Carotid Plaques and Plasma Associates With Plaque Instability

Nishi, Kyoko; Itabe, Hiroyuki; Uno, Masaaki; Kitazato, Keiko T.; Horiguchi, Hironori; Shinno, Kiyohito; Saijo, Nagahiro

doi:10.1161/01.atv.0000033829.14012.18

Cited by 376 publications

(240 citation statements)

References 27 publications

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“…Next, we asked whether the changes observed in vivo would also be observed in vitro in peritoneal macrophages treated with oxLDL. It was reported that oxLDL in human endarterectomy specimens was nearly 70 times higher than plasma oxLDL in the same patients 33. Thus, given that measurements of oxLDL concentrations within mouse atherosclerotic lesions are extremely challenging, we performed a dose‐response study that included a low dose of oxLDL close to the circulating levels (1 μg/mL) and 2 higher doses of 50 and 100 μg/mL.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate‐Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation

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Son

Yechoor

et al. 2016

JAHA

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BackgroundFoam cells are central to two major pathogenic processes in atherogenesis: cholesterol buildup in arteries and inflammation. The main underlying cause of cholesterol deposition in arteries is hypercholesterolemia. This study aimed to assess, in vivo, whether elevated plasma cholesterol also alters the inflammatory balance of foam cells.Methods and ResultsApolipoprotein E–deficient mice were fed regular mouse chow through the study or were switched to a Western‐type diet (WD) 2 or 14 weeks before death. Consecutive sections of the aortic sinus were used for lesion quantification or to isolate RNA from foam cells by laser‐capture microdissection (LCM) for microarray and quantitative polymerase chain reaction analyses. WD feeding for 2 or 14 weeks significantly increased plasma cholesterol, but the size of atherosclerotic lesions increased only in the 14‐week WD group. Expression of more genes was affected in foam cells of mice under prolonged hypercholesterolemia than in mice fed WD for 2 weeks. However, most transcripts coding for inflammatory mediators remained unchanged in both WD groups. Among the main players in inflammatory or immune responses, chemokine (C‐X‐C motif) ligand 13 was induced in foam cells of mice under WD for 2 weeks. The interferon‐inducible GTPases, guanylate‐binding proteins (GBP)3 and GBP6, were induced in the 14‐week WD group, and other GBP family members were moderately increased.ConclusionsOur results indicate that acceleration of atherosclerosis by hypercholesterolemia is not linked to global changes in the inflammatory balance of foam cells. However, induction of GBPs uncovers a novel family of immune modulators with a potential role in atherogenesis.

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Section: Resultsmentioning

confidence: 99%

Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate‐Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation

Goo

Son

Yechoor

et al. 2016

JAHA

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“…[5][6][7] In humans, plaque specimens from carotid and coronary arteries are significantly enriched in OxLDL 1,3 and become depleted in OxLDL after treatment with statins. 8 In particular, unstable plaques appear to be preferentially enriched in OxLDL, 9,10 and OxLDL in plasma has been shown to be associated with acute coronary syndromes 9,11,12 and endothelial dysfunction. 13,14 In the present study, we measured plasma levels of several OxLDL markers immediately before and serially up to 6 months after percutaneous coronary intervention (PCI) to evaluate the role of OxLDL in PCI.…”

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confidence: 99%

Percutaneous Coronary Intervention Results in Acute Increases in Oxidized Phospholipids and Lipoprotein(a)

et al. 2004

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Background-This study was performed to assess whether oxidized low-density lipoprotein (OxLDL) levels are elevated after percutaneous coronary intervention (PCI). Methods and Results-Patients (nϭ141) with stable angina pectoris undergoing PCI had serial venous blood samples drawn before PCI, after PCI, and at 6 and 24 hours, 3 days, 1 week, and 1, 3, and 6 months. Plasma levels of OxLDL-E06, a measure of oxidized phospholipid (OxPL) content on apolipoprotein B-100 detected by antibody E06, lipoprotein(a) [Lp(a)], autoantibodies to malondialdehyde (MDA)-LDL and copper-oxidized LDL (Cu-OxLDL), and apolipoprotein B-100 -immune complexes (apoB-IC) were measured. OxLDL-E06 and Lp(a) levels significantly increased immediately after PCI by 36% (PϽ0.0001) and 64% (PϽ0.0001), respectively, and returned to baseline by 6 hours. In vitro immunoprecipitation of Lp(a) from selected plasma samples showed that almost all of the OxPL detected by E06 was bound to Lp(a) at all time points, except in the post-PCI sample, suggesting independent release and subsequent reassociation of OxPL with Lp(a) by 6 hours. Strong correlations were noted between OxLDL-E06 and Lp(a) (rϭ0.68, PϽ0.0001). MDA-LDL and Cu-OxLDL autoantibodies decreased, whereas apoB-IC levels increased after PCI, but both returned to baseline by 6 hours. Subsequently, IgM autoantibodies increased and peaked at 1 month and then returned to baseline, whereas IgG autoantibodies increased steadily over 6 months. Conclusions-PCI results in acute plasma increases of Lp(a) and OxPL and results in short-term and long-term immunologic responses to OxLDL. OxPL that are released or generated during PCI are transferred to Lp(a), suggesting that Lp(a) may contribute acutely to a protective innate immune response. In settings of enhanced oxidative stress and chronically elevated Lp(a) levels, the atherogenicity of Lp(a) may stem from its capacity as a carrier of proinflammatory oxidation byproducts.

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“…19 In 1994, Itabe et al 20 raised a monoclonal antibody directed against oxLDL (FOH1a/DLH3) to investigate whether oxLDL was synthesized in foam cells in vitro and in vivo. [20][21][22][23] Despite the close relationship between the level of oxLDL expression and the induction of apoptosis, there have been only a few studies in vivo on the role of oxLDL in the apoptosis of intimal cells. 9,11 Furthermore, the difference in distribution of apoptosis between smooth muscle cells and macrophages has not yet been examined with respect to atherosclerosis.…”

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confidence: 99%

Role of macrophage and smooth muscle cell apoptosis in association with oxidized low-density lipoprotein in the atherosclerotic development

et al. 2005

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To examine the role of the apoptosis of macrophages and smooth muscle cells in the development of atherosclerosis, human aortic tissues with intimal lesions were immunostained with antibodies against terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL), single-stranded DNA (clone F7-26), and active caspase-3. Apoptotic cells were detected in the intima using both TUNEL and singlestranded DNA, however, the latter method was the more sensitive one for detecting apoptotic cells in the early stages of atherosclerosis. The number of apoptotic cells increased as the disease progressed. It implies that the apoptosis of intimal cells is involved in the formation of atherosclerotic lesions. In addition, quantitative analyses of the cell types undergoing apoptosis using double-immunostaining revealed that the susceptibility of macrophages and smooth muscle cells to apoptosis was greater specifically in atheroma than in the other atherosclerotic lesions, and macrophages were more susceptible to apoptosis than smooth muscle cells. The frequency and spatial distribution of oxidized low-density lipoprotein (oxLDL) (FOH1a/DLH3)-positive cells were examined by immunohistochemistry, and the results resembled those of apoptotic cells. The number of oxLDLpositive cells in the intima significantly correlated with the susceptibility of smooth muscle cells, but not with that of macrophages, to apoptosis. These results suggest that oxLDL affects the apoptosis of smooth muscle cells during the atherosclerotic development.

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Oxidized LDL in Carotid Plaques and Plasma Associates With Plaque Instability

Cited by 376 publications

References 27 publications

Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate‐Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation

Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate‐Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation

Percutaneous Coronary Intervention Results in Acute Increases in Oxidized Phospholipids and Lipoprotein(a)

Role of macrophage and smooth muscle cell apoptosis in association with oxidized low-density lipoprotein in the atherosclerotic development

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