Adipophilin Expression Is Increased in Symptomatic Carotid Atherosclerosis

Nuotio, Krista; Isoviita, P.M.; Saksi, Jani; Ijäs, Petra; Pitkäniemi, Janne; Sonninen, Riitta; Soinne, Lauri; Saimanen, Eija; Salonen, Oili; Kovanen, Petri T.; Kaste, Markku; Lindsberg, Perttu J.

doi:10.1161/strokeaha.106.478867

Cited by 43 publications

(32 citation statements)

References 35 publications

(38 reference statements)

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Section: Methodsmentioning

confidence: 99%

“…4,5 Quantitative real-time reverse-transcription polymerase chain reaction was performed using Assays-on-Demand Gene Expression Products and an ABI PRISM 7000 Sequence Detection System (Applied Biosystems). Relative CD36 and ABCA1 gene expression was determined using the comparative CT method and standard curve method, respectively, and expression of ␤-actin was used for normalization.…”

Section: Methodsmentioning

confidence: 99%

“…To adjust for confounding factors such as age, gender, body mass index, blood low-density lipoprotein concentration, and the amount of plaque macrophages, 8 a multinomial logistic regression model was used to explore the association between regions of interest levels and ABCA1/CD36, as described in detail previously. 4 Statistical analyses were performed using SPSS (version 14.0).…”

Section: Methodsmentioning

confidence: 99%

“…To obtain detailed distribution data from the protein expression, we analyzed separate regions of interest of the entire immunostained section, as described previously. 4 For details on immunohistochemical methods, please see Supplemental Figure I, available online at http://stroke.ahajournals.org.Total RNA was extracted from a longitudinal slice containing a section with tightest stenosis, as previously described. 4,5 Quantitative real-time reverse-transcription polymerase chain reaction was performed using Assays-on-Demand Gene Expression Products and an ABI PRISM 7000 Sequence Detection System (Applied Biosystems).…”

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confidence: 99%

“…4 For details on immunohistochemical methods, please see Supplemental Figure I, available online at http://stroke.ahajournals.org.…”

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confidence: 99%

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An Imbalance Between CD36 and ABCA1 Protein Expression Favors Lipid Accumulation in Stroke-Prone Ulcerated Carotid Plaques

Isoviita

Nuotio

Saksi

et al. 2010

Stroke

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Background-CD36 is a macrophage scavenger receptor mediating the uptake of modified lipoproteins, whereas the ABCA1 transporter counteracts this effect by mediating cellular lipid efflux. Based on a DNA microarray, we previously found that the CD36 and ABCA1 genes were overexpressed in symptom-causing carotid plaques (CP) compared with nonsymptomcausing CP. To evaluate their role in CP destabilization, we conducted detailed immunohistochemical studies on the localization of lipids, CD36 and ABCA1 proteins, extravasated red blood cells, and atheromatous/necrotic tissue. Methods-Ninety-two high-grade (Ͼ70%) stenosing CP obtained from carotid endarterectomy were Oil-red-O-stained for evaluation of neutral lipids. Subgroups of nonsymptom-causing and symptom-causing CP (nϭ42) were further analyzed by immunostaining adjacent histological sections against CD36 and ABCA1 and examining them microscopically. Results-When compared with nonsymptom-causing CP, the amount of extracellular lipid and the expression of CD36 protein were elevated in symptom-causing CP, but no difference was found in ABCA1 expression. These observations were also confirmed when ulcerated and nonulcerated CP were compared. In ulcerated CP, CD36 protein expression was higher than that of ABCA1, and the opposite was true in nonulcerated CP. CD36 colocalized with extravasated red blood cells and atheromatous or necrotic areas in the various types of CP. A dvanced atherosclerotic plaques in the internal carotid artery wall are considered as a clinical threat potentially leading to stroke. A spectrum of factors underlying the final destabilization and rupture of the plaques has been studied, but distinguishing between high-risk and low-risk plaques is still an enigma. However, one of the morphological features of high-risk plaques seems to be a vast lipid-filled core, the formation of which is fueled by the death of engorged lipid-filled macrophage foam cells. Conclusions-OurIn a genome-wide microarray expression study of advanced carotid plaques (CP), we discovered that the transformation of a CP from nonsymptom-causing to symptomcausing coincided with increased expression of macrophage adipophilin, 4 a lipid-loading marker. We also found that CD36 and ABCA1 genes were overexpressed in symptomcausing CP, and the result was replicated by real-time reverse-transcription polymerase chain reaction for CD36 (Saksi et al, unpublished data, 2009). Interestingly, both CD36 and ABCA1 seem to play an important role in balancing macrophage lipid intake and efflux. Oxidized low-density lipoprotein-scavenging CD36, a multifunctional membrane glycoprotein, is considered essential for foam cell formation, 1 and its expression is further stimulated by its own ligand. 2 This vicious cycle potentially leading to fatal cholesterol overload is partly inhibited by ABCA1, a membrane transporter protein of ATP-binding cassette (ABC) family, widely supported in its atheroprotectiveness, removing free cholesterol and phospholipids, and necessary for the initiation of macrophag...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

“…4 For details on immunohistochemical methods, please see Supplemental Figure I, available online at http://stroke.ahajournals.org.…”

mentioning

confidence: 99%

See 3 more Smart Citations

An Imbalance Between CD36 and ABCA1 Protein Expression Favors Lipid Accumulation in Stroke-Prone Ulcerated Carotid Plaques

Isoviita

Nuotio

Saksi

et al. 2010

Stroke

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Evaluation Criteria of Carotid Artery Atherosclerosis: Noninvasive Multimodal Imaging and Molecular Imaging

Sharma

Katz²

2010

Atherosclerosis Disease Management

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Gene expression differences between stroke-associated and asymptomatic carotid plaques

et al. 2011

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Atherosclerotic carotid stenosis is an important risk factor for stroke. Carotid plaques (CPs) causing stroke may present a distinct type of molecular pathology compared with transient ischemic attack (TIA)-associated or asymptomatic plaques. We compared the gene expression profiles of CPs from stroke patients (n = 12) and asymptomatic patients (n = 9), both with similar risk factors and severity of carotid stenosis (>70%). Sixty probes showed over 1.5-fold expression difference at 5% false discovery rate. Functional clustering showed enrichment of genes in 51 GO categories and seven pathways, the most significant of which relate to extracellular-matrix interaction, PPAR gamma signaling, scavanger receptor activity, and lysosomal activity. Differential expression of ten genes was confirmed in an extended replication group (n = 43), where the most significant expression differences were found in CD36 (2.1-fold change, p = 0.005), CD163 (1.7-fold change, p = 0.007) and FABP4 (2.2-fold change, p = 0.015). These include four genes not previously linked to plaque destabilization: GLUL (2.2-fold change, p = 0.016), FUCA1 (2.2-fold change, p = 0.025), IL1RN (1.6-fold change, p = 0.034), and S100A8 (2.5-fold change, p = 0.047). Strong correlations were found to plaque ulceration, plaque hemorrhage, and markers of apoptosis and proliferation (activated caspase 3, TUNEL, and Ki67). Protein expression of these genes was confirmed by immunohistochemistry and was found in the atheromatous areas of CPs critical for plaque destabilization. This study presents a comprehensive transcriptional analysis of stroke-associated CPs and demonstrates a significant transcriptome difference between stroke-associated and asymptomatic CPs. Follow-up studies on the identified genes are needed to define whether they could be used as biomarkers of symptomatic CPs or have a role in plaque destabilization.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-011-0773-z) contains supplementary material, which is available to authorized users.

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Adipophilin Expression Is Increased in Symptomatic Carotid Atherosclerosis

Abstract: Background and Purpose-Adipophilin is an adipose differentiation-related protein expressed in lipid-containing cells.Using DNA microarray analysis, we previously found the adipophilin gene (ADFP) to be overexpressed in symptomatic carotid plaques (CP

Cited by 43 publications

References 35 publications

An Imbalance Between CD36 and ABCA1 Protein Expression Favors Lipid Accumulation in Stroke-Prone Ulcerated Carotid Plaques

An Imbalance Between CD36 and ABCA1 Protein Expression Favors Lipid Accumulation in Stroke-Prone Ulcerated Carotid Plaques

Evaluation Criteria of Carotid Artery Atherosclerosis: Noninvasive Multimodal Imaging and Molecular Imaging

Gene expression differences between stroke-associated and asymptomatic carotid plaques

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