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Macrophage heterogeneity and cholesterol homeostasis: classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL.

ABSTRACT: Macrophages are centrally involved during atherosclerosis development and are the predominant cell type that accumulates cholesterol in the plaque. Macrophages however, are heterogeneous in nature reflecting a variety of microenvironments and different phenotypes may be more prone to contribute towards atherosclerosis progression. Using primary human monocyte-derived macrophages, we sought to evaluate one aspect of atherogenic potential of different macrophage phenotypes by determining their propensity to associate with and accumulate oxidized low density lipoprotein (oxLDL). Classically-activated macrophages treated simultaneously with interferon ? (IFN?) and tumor necrosis factor ? (TNF?) associated with less oxLDL and accumulated less cholesterol compared to untreated controls. The combined treatment of IFN? and TNF? reduced the mRNA expression of CD36 and the expression of both cell surface CD36 and macrophage scavenger receptor 1 (MSR1) protein. Under oxLDL loaded conditions, IFN? and TNF? did not reduce macrophage protein expression of the transcription factor peroxisome proliferator-actived receptor ? (PPAR?) which is known to positively regulate CD36 expression. However, macrophages treated with IFN? attenuated the ability of the PPAR?-specific agonist rosiglitazone from upregulating cell surface CD36 protein expression. Our results demonstrate that the observed reduction of cholesterol accumulation in macrophages treated with IFN? and TNF? following oxLDL treatment was due at least in part to reduced cell surface CD36 and MSR1 protein expression.

SUBMITTER: Chu EM

PROVIDER: S-EPMC3569505 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Macrophage heterogeneity and cholesterol homeostasis: classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL.

Chu Eugene M EM Tai Daven C DC Beer Jennifer L JL Hill John S JS

Biochimica et biophysica acta 20121108 2

Macrophages are centrally involved during atherosclerosis development and are the predominant cell type that accumulates cholesterol in the plaque. Macrophages however, are heterogeneous in nature reflecting a variety of microenvironments and different phenotypes may be more prone to contribute towards atherosclerosis progression. Using primary human monocyte-derived macrophages, we sought to evaluate one aspect of atherogenic potential of different macrophage phenotypes by determining their pro ...[more]

PMID: 23142249

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Project description:Atherosclerosis (AS), a major cause of cardiovascular disease, has developed into a serious challenge to the health system. The long non?coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is associated with the pathogenesis of AS. However, whether MALAT1 can affect cholesterol accumulation in macrophages during AS progression, and the potential molecular mechanism involved in this progression have not been elucidated. In the present study, the mRNA expression level of MALAT1 was measured using reverse transcription?quantitative PCR (RT?qPCR) and the protein expression level was detected via western blot analysis. Oil Red O staining was used for detecting lipid accumulation in macrophages. Bioinformatics, dual?luciferase reporter and RT?qPCR assays were used to investigate the relationship between MALAT1 and the microRNA (miR)?17?5p/ATP?binding cassette transporter A1 (ABCA1) axis. The present results suggested that the MALAT1 expression level was significantly decreased in patients with AS and in oxidized low?density lipoprotein (ox?LDL)?stimulated macrophages. Knockdown of MALAT1 increased ox?LDL uptake, lipid accumulation and the total cholesterol (T?CHO) level in ox?LDL?induced macrophages. In addition, MALAT1 inhibition significantly decreased the mRNA and protein expression levels of scavenger receptor (SR) class B member 1, apolipoprotein E (ApoE) and ABCA1. However, MALAT1 increased the expression level of SR class A. Subsequently, the present study investigated whether MALAT1 could target miR?17?5p to regulate the expression level of ABCA1, which is involved in cholesterol efflux from macrophages. The present results suggested that inhibition of miR?17?5p reversed the effects of MALAT1 knockdown on T?CHO content, and protein expression levels of ApoE and ABCA1 in ox?LDL?stimulated macrophages. In summary, knockdown of MALAT1 may promote cholesterol accumulation by regulating the miR?17?5p/ABCA1 axis in ox?LDL?induced THP?1 macrophages.

Dataset Information

Macrophage heterogeneity and cholesterol homeostasis: classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL.

Publications

Macrophage heterogeneity and cholesterol homeostasis: classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL.

Similar Datasets

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