Drug-induced macrophage autophagy in atherosclerosis: for better or worse?

Martinet, Wim; Meyer, Inge De; Verheye, Stefan; Schrijvers, Dorien M.; Timmermans, Jean‐Pierre; Meyer, Guido

doi:10.1007/s00395-012-0321-1

Cited by 49 publications

(35 citation statements)

References 83 publications

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“…Evidence showing that atherosclerosis progression is accompanied by increasing defects in macrophage autophagy provides further enthusiasm regarding the possibility that enhancement of macrophage autophagy may be an effective way to reduce or reverse atherosclerosis. However, currently known autophagy inducers, including mTOR inhibitors and toll-like receptor (TLR)7 ligands, are less than ideal therapeutics in the context of atherosclerosis, due to hyperlipidemic (24) and pro-inflammatory effects, respectively (25). Therefore, the search for new macrophage autophagy stimuli is urgent.…”

Section: Mtt Assaymentioning

confidence: 99%

Ursolic acid enhances macrophage autophagy and attenuates atherogenesis

Leng

Iwanowycz

Saaoud

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org recycled for downstream metabolism (1). Among the three major kinds of autophagy, macroautophagy, microautophagy, and chaperone-mediated autophagy, macroautophagy is the most prevalent form and, thus, commonly referred to as autophagy (2, 3). Over the past decade, research efforts regarding this ancient biological process have been revived due to the realization that alterations in autophagy play crucial pathological roles in many diseases (4, 5) for which current therapeutic means are limited. While many basic aspects of autophagy have been unraveled, little has been translated into clinical benefit, and no autophagy-modulating therapies have been approved for clinical use.The autophagy process starts with the formation of a double-membrane autophagosome, which engulfs cytoplasmic materials. Autophagosomes are targeted to the lysosomal compartment and single-membrane autolysosomes are generated in which the sequestered cargos are degraded in the highly acidic environment and the resulting simple products are reused (6, 7). There are many molecules involved in autophagy, including Beclin-1 (involved in vesicle nucleation); Atg5, Atg7, and Atg16L1 (involved in vesicle elongation); and LC3 (involved in the expansion of autophagosome membrane and autophagosome-lysosome fusion) (8). Autophagy occurs in almost all cell types, including macrophages. Macrophages primarily use phagocytosis as the first line of defense against exogenous pathogens and endogenous waste products. They adopt autophagy to process bulky materials (e.g., damaged mitochondria and excessive lipids) in unfavorable microenvironments, thus mitigating cytotoxicity. Recently, autophagy has been shown to play a critical role in inflammatory responses in macrophages by interacting with inflammasomes or directly targeting pro-interleukin Abstract Macrophage autophagy has been shown to be protective against atherosclerosis. We previously discovered that ursolic acid (UA) promoted cancer cell autophagy. In the present study, we aimed to examine whether UA enhances macrophage autophagy in the context of atherogenesis. Cell culture study showed that UA enhanced autophagy of macrophages by increasing the expression of Atg5 and Atg16l1, which led to altered macrophage function. UA reduced pro-interleukin (IL)-1 protein levels and mature IL-1 secretion in macrophages in response to lipopolysaccharide (LPS), without reducing IL-1 mRNA expression. Confocal microscopy showed that in LPS-treated macrophages, UA increased LC3 protein levels and LC3 appeared to colocalize with IL-1. In cholesterolloaded macrophages, UA increased cholesterol efflux to apoAI, although it did not alter mRNA or protein levels of ABCA1 and ABCG1. Electron microscopy showed that UA induced lipophagy in acetylated LDL-loaded macrophages, which may result in increased cholesterol ester hydrolysis in autophagolysosomes and presentation of free cholesterol to the cell membrane. In LDLR / mice fed a Western diet to induce atherogenesi...

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Section: Mtt Assaymentioning

confidence: 99%

Ursolic acid enhances macrophage autophagy and attenuates atherogenesis

Leng

Iwanowycz

Saaoud

et al. 2016

Journal of Lipid Research

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“…The morbidity and mortality rates of AS is increasing. Hyperlipidemia is an important cause of pathological changes in AS, and lipid metabolism disorders and abnormal lipoprotein composition are key factors in the pathogenesis of AS (Hyafil et al, 2012;Martinet et al, 2012;Zhao et al, 2012). Safflower yellow (SY), a natural yellow pigment extracted from safflower petals, is a chalcone compound.…”

Section: Introductionmentioning

confidence: 99%

Hypolipidemic effect of safflower yellow and primary mechanism analysis

Wang¹,

Ren²,

Ma³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. We examined the hypolipidemic effect of safflower yellow (SY) on hyperlipidemic mice and its influence on the biological synthesis of cholesterol in cells. Over 4 weeks, the levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and highdensity lipoprotein cholesterol in serum were detected using a kit; mouse liver samples were acquired for paraffin sections, and mouse liver cells were observed under light microscope. Chinese hamster ovary cells were cultured in vitro, and an amphotericin B-cell model was adopted to observe the inhibitory effect of SY on the biological synthesis of intracellular cholesterol. An enzyme-linked immunosorbent assay was used to detect the survival rate of Chinese hamster ovary cells. The middle and high doses of SY significantly reduced the levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol in the serum of hyperlipidemic mice and low-density lipoprotein cholesterol/ high-density lipoprotein cholesterol ratio (P < 0.05), and the fatty liver of hyperlipidemic mice was significantly alleviated. SY had a protective 6271 Hypolipidemic effect of safflower yellow ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 6270-6278 (2015) effect on Chinese hamster ovary cells following amphotericin B injury (P < 0.01). SY exerts significant hypolipidemic effects and prevents fatty liver in a mechanism associated with inhibition of the biosynthesis of intracellular cholesterol.

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“…The present study reported that, besides decreasing ox-LDL-induced cholesterol accumulation, simvastatin intensified ox-LDL-induced macrophage autophagy. However, it remains noteworthy that drugs may directly induce macrophage autophagy in atherosclerosis, and certain drug-induced macrophage autophagy promotes a stable plaque phenotype (22). The results of the present study showed that simvastatin may directly induce macrophage autophagy, albeit only marginally.…”

Section: Discussionmentioning

confidence: 40%

“…In mammalian cells there are two types of autophagy: mTOR-dependent and mTOR-independent autophagy (22). Wei et al (14) demonstrated that simvastatin induced autophagy through inhibition of Rac1-mTOR signaling in coronary arterial myocytes.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin enhances oxidized-low density lipoprotein-induced macrophage autophagy and attenuates lipid aggregation

Huang

Jin

Yan

et al. 2014

Molecular Medicine Reports

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Abstract. Macrophage autophagy exerts a protective effect in advanced atherosclerosis. It has previously been reported that oxidized low-density lipoprotein (ox-LDL) induces autophagy in endothelial cells, and simvastatin enhances autophagy in coronary arterial myocytes. However, it is currently unknown whether ox-LDL induces autophagy in macrophages, or whether simvastatin affects macrophage autophagy in atherosclerosis. The present study demonstrated that ox-LDL induced lipid accumulation in the J774A.1 macrophage cell line, in a dose-dependent manner, as determined by oil red O staining. Ox-LDL also induced autophagy in the J774A.1 cells, by converting microtubule-associated protein 1 light chain 3 (LC3) I to LC3 II, which is a well-known autophagy marker. Notably, treatment of the cells with simvastatin elevated ox-LDL-induced macrophage autophagy, this was detected through the conversion of LC3 I to LC3 II and the increased expression of Beclin1, another autophagy marker. Furthermore, it was shown that stimulation with ox-LDL led to the redistribution of green fluorescent protein (GFP)-LC3 from diffusion distribution, to the formation of puncta in the J774A.1 cells. Simvastatin promoted the ox-LDL-induced formation of GFP-LC3 puncta, as detected by confocal laser scanning microscopy. Simvastatin was also shown to inhibit ox-LDL-induced cholesterol accumulation in the J774A.1 cells, as observed by oil red O staining and CHOD-PAP assay. These results suggest that simvastatin may enhance ox-LDL-induced macrophage autophagy and attenuate lipid aggregation. IntroductionActivation, dysfunction and structural alterations of the arterial endothelium results in the subendothelial retention of oxidized low-density lipoprotein (ox-LDL) from the plasma, thereby promoting the development and progression of atherosclerosis (1). Activated endothelial cells secrete chemokines, and subsequently express adhesion molecules, which may facilitate the recruitment of leukocytes, from the blood into the arterial wall (2). Of the leukocytes, monocytes are a critical cell type that contribute to the formation of atherosclerotic plaques. In the intima, migrated monocytes differentiate into macrophages, which engulf ox-LDL to form cholesterol-laden foam cells (3).Autophagy is a conserved catabolic process in which cytoplasmic material is delivered to the lysosomal machinery for degradation and recycling. It is well-known that autophagy occurs in advanced atherosclerotic plaques (4-6), and that macrophage autophagy exerts a protective effect in advanced atherosclerosis (7). Previous studies have shown that ox-LDL may induce autophagy in endothelial cells, leading to the degradation of ox-LDL through autolysosomes (8,9). However, little is currently known about whether ox-LDL may induce autophagy in macrophages.Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Statins impede cholesterol biosynthesis, therefore reducing blood cholesterol levels. As well as lowering lipid levels, statins have been demons...

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Drug-induced macrophage autophagy in atherosclerosis: for better or worse?

Cited by 49 publications

References 83 publications

Ursolic acid enhances macrophage autophagy and attenuates atherogenesis

Ursolic acid enhances macrophage autophagy and attenuates atherogenesis

Hypolipidemic effect of safflower yellow and primary mechanism analysis

Simvastatin enhances oxidized-low density lipoprotein-induced macrophage autophagy and attenuates lipid aggregation

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