LDL inhibits the mediation of cholesterol efflux from macrophage foam cells by apoA-I-containing lipoproteins. A putative mechanism for foam cell formation.

oxLDL is involved in the pathogenesis of atherosclerotic lesions through cholesterol accumulation in macrophage foam cells. Andrographolide, the bioactive component of Andrographis paniculata, possesses several biological activities such as anti-inflammatory, anti-oxidant, and anticancer functions. Scavenger receptors (SRs), including class A SR (SR-A) and CD36, are responsible for the internalization of oxLDL. In contrast, receptors for reverse cholesterol transport, including ABCA1 and ABCG1, mediate the efflux of cholesterol from macrophage foam cells. Transcription factor liver X receptor [Formula: see text] (LXR[Formula: see text] plays a key role in lipid metabolism and inflammation as well as in the regulation of ABCA1 and ABCG1 expression. Because of the contribution of inflammation to macrophage foam cell formation and the potent anti-inflammatory activity of andrographolide, we hypothesized that andrographolide might inhibit oxLDL-induced macrophage foam cell formation. The results showed that andrographolide reduced oxLDL-induced lipid accumulation in macrophage foam cells. Andrographolide decreased the mRNA and protein expression of CD36 by inducing the degradation of CD36 mRNA; however, andrographolide had no effect on SR-A expression. In contrast, andrographolide increased the mRNA and protein expression of ABCA1 and ABCG1, which were dependent on LXR[Formula: see text]. Andrographolide enhanced LXR[Formula: see text] nuclear translocation and DNA binding activity. Treatment with the LXR[Formula: see text] antagonist GGPP and transfection with LXR[Formula: see text] siRNA reversed the ability of andrographolide to stimulate ABCA1 and ABCG1 protein expression. In conclusion, inhibition of CD36-mediated oxLDL uptake and induction of ABCA1- and ABCG1-dependent cholesterol efflux are two working mechanisms by which andrographolide inhibits macrophage foam cell formation, which suggests that andrographolide could be a potential candidate to prevent atherosclerosis.

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Interplay of Autophagy Inducer Rapamycin and Proteasome Inhibitor MG132 in Reduction of Foam Cell Formation and Inflammatory Cytokine Expression

Cell Transplantation ◽

10.1177/0963689718786229 ◽

2018 ◽

Vol 27 (8) ◽

pp. 1235-1248

Author(s):

Wei Zhang ◽

Wan Xu ◽

Wenli Chen ◽

Quan Zhou

Keyword(s):

Molecular Mechanism ◽

Proteasome Inhibitor ◽

Foam Cell ◽

Cell Formation ◽

Foam Cells ◽

Oxidative Modification ◽

Raw 264.7 Cells ◽

Foam Cell Formation ◽

Proteasome Inhibitor Mg132 ◽

Macrophage Foam Cells

MG132 is a pivotal inhibitor of the ubiquitin-proteasome system (UPS), and rapamycin (RAPA) is an important inducer of autophagy. MG132 and RAPA have been shown to be effective agents that can cure multiple autoimmune diseases by reducing inflammation. Although individual MG132 and RAPA showed protective effects for atherosclerosis (AS), the combined effect of these two drugs and its molecular mechanism are still unclear. In this article we investigate the regulation of oxidative modification of low-density lipoprotein (ox-LDL) stress and foam cell formation in the presence of both proteasome inhibitor MG132 and the autophagy inducer RAPA to uncover the molecular mechanism underlying this process. We established the foam cells model by ox-LDL and an animal model. Then, we tested six experimental groups of MG132, RAPA, and 3MA drugs. As a result, RAPA-induced autophagy reduces accumulation of polyubiquitinated proteins and apoptosis of foam cells. The combination of MG132 with RAPA not only suppressed expression of the inflammatory cytokines and formation of macrophage foam cells, but also significantly affected the NF-κB signaling pathway and the polarization of RAW 264.7 cells. These data suggest that the combination of proteasome inhibitor and autophagy inducer ameliorates the inflammatory response and reduces the formation of macrophage foam cells during development of AS. Our research provides a new way to suppress vascular inflammation and stabilize plaques of late atherosclerosis.

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Foam Cells as Therapeutic Targets in Atherosclerosis with a Focus on the Regulatory Roles of Non-Coding RNAs

International Journal of Molecular Sciences ◽

10.3390/ijms22052529 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2529

Author(s):

Amin Javadifar ◽

Sahar Rastgoo ◽

Maciej Banach ◽

Tannaz Jamialahmadi ◽

Thomas P. Johnston ◽

...

Keyword(s):

Lipid Metabolism ◽

Foam Cell ◽

Cell Formation ◽

Foam Cells ◽

Foam Cell Formation ◽

Special Focus ◽

Lipid Uptake ◽

Therapeutic Goals ◽

Expression Of Genes

Atherosclerosis is a major cause of human cardiovascular disease, which is the leading cause of mortality around the world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation of lipid metabolism, development of an environment characterized by oxidative stress and improper immune responses. Accordingly, the expansion of novel targets for the treatment of atherosclerosis is necessary. In this study, we focus on the role of foam cells in the development of atherosclerosis. The specific therapeutic goals associated with each stage in the formation of foam cells and the development of atherosclerosis will be considered. Processing and metabolism of cholesterol in the macrophage is one of the main steps in foam cell formation. Cholesterol processing involves lipid uptake, cholesterol esterification and cholesterol efflux, which ultimately leads to cholesterol equilibrium in the macrophage. Recently, many preclinical studies have appeared concerning the role of non-encoding RNAs in the formation of atherosclerotic lesions. Non-encoding RNAs, especially microRNAs, are considered regulators of lipid metabolism by affecting the expression of genes involved in the uptake (e.g., CD36 and LOX1) esterification (ACAT1) and efflux (ABCA1, ABCG1) of cholesterol. They are also able to regulate inflammatory pathways, produce cytokines and mediate foam cell apoptosis. We have reviewed important preclinical evidence of their therapeutic targeting in atherosclerosis, with a special focus on foam cell formation.

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Abstract 43: Cholesterol Efflux Pathways Suppress Inflammasome Activation in Mice and Humans

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.43 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Marit Westerterp ◽

Panagiotis Fotakis ◽

Mireille Ouimet ◽

Andrea E Bochem ◽

Hanrui Zhang ◽

...

Keyword(s):

Plasma Levels ◽

Cholesterol Efflux ◽

Foam Cell ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cell Formation ◽

Inflammasome Activation ◽

Loss Of Function ◽

Caspase 1 ◽

Macrophage Cholesterol Efflux

Plasma high-density-lipoprotein (HDL) has several anti-atherogenic properties, including its key role in functioning as acceptor for ATP-binding cassette A1 and G1 (ABCA1 and ABCG1) mediated cholesterol efflux. We have shown previously that macrophage Abca1/g1 deficiency accelerates atherosclerosis, by enhancing foam cell formation and inflammatory cytokine expression in atherosclerotic plaques. Macrophage cholesterol accumulation activates the inflammasome, leading to caspase-1 cleavage, required for IL-1β and IL-18 secretion. Several studies have suggested that inflammasome activation accelerates atherogenesis. We hypothesized that macrophage Abca1/g1 deficiency activates the inflammasome. In Ldlr -/- mice fed a Western type diet (WTD), macrophage Abca1/g1 deficiency increased IL-1β and IL-18 plasma levels (2-fold; P <0.001), and induced caspase-1 cleavage. Deficiency of the inflammasome components Nlrp3 or caspase-1 in macrophage Abca1/g1 knockouts reversed the increase in plasma IL-18 levels ( P <0.001), indicating these changes were inflammasome dependent. We found that macrophage Abca1/g1 deficiency induced caspase-1 cleavage in splenic CD115 + monocytes and CD11b + macrophages. While mitochondrial ROS production or lysosomal function were not affected, macrophage Abca1/g1 deficiency led to an increased splenic population of monocytes (2.5-fold; P <0.01). Monocytes secrete ATP, and as a result, ATP secretion from total splenic cells was increased (2.5-fold; P <0.01), likely contributing to inflammasome activation. Caspase-1 deficiency decreased atherosclerosis in macrophage Abca1/g1 deficient Ldlr -/- mice fed WTD for 8 weeks (225822 vs 138606 μm 2 ; P <0.05). Of therapeutic interest, one injection of reconstituted HDL (100 mg/kg) in macrophage Abca1/g1 knockouts decreased plasma IL-18 levels ( P <0.05). Tangier disease patients, with a homozygous loss-of-function for ABCA1, showed increased IL-1β and IL-18 plasma levels (3-fold; P <0.001), suggesting that cholesterol efflux pathways also suppress inflammasome activation in humans. These findings suggest that macrophage cholesterol efflux pathways suppress inflammasome activation, possibly contributing to the anti-atherogenic effects of HDL treatment.

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Niacin‐induced enhancement of lysosomal cholesterol efflux in macrophages through CD38 ‐ NAADP signaling pathway: implication in reduced foam cell formation (671.6)

The FASEB Journal ◽

10.1096/fasebj.28.1_supplement.671.6 ◽

2014 ◽

Vol 28 (S1) ◽

Author(s):

Fan Zhang ◽

Qiufang Zhang ◽

Ningjun Li ◽

Pin‐Lan Li

Keyword(s):

Signaling Pathway ◽

Cholesterol Efflux ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation

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Abstract 57: The Epigenetic Enzyme Kdm6b Controls the Pro-Fibrotic Transcriptome Signature of Foam Cells

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.57 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Annette E Neele ◽

Koen H Prange ◽

Marten A Hoeksema ◽

Saskia van der Velden ◽

Tina Lucas ◽

...

Keyword(s):

Foam Cell ◽

Smooth Muscle Actin ◽

Cell Formation ◽

Atherosclerotic Lesion ◽

Foam Cells ◽

Foam Cell Formation ◽

Cell Phenotype ◽

Sequencing Analysis ◽

Dependent Manner ◽

Alpha Smooth Muscle Actin

Aim: Foam cells are a key hallmark of atherosclerotic lesion formation. Within the atherosclerotic lesion macrophages scavenge modified lipoproteins and thereby acquire their foam cell characteristics. Besides their foam cell phenotype, macrophages can have specific inflammation regulatory functions in atherosclerotic lesions. Epigenetic pathways are crucial for monocyte to macrophage differentiation and activation. The H3K27 demethylase Kdm6b (also known as Jmjd3) is regulated in response to various triggers and regulates several modes of macrophage activation. Given the crucial role of macrophage foam cells in atherosclerosis, we here studied Kdm6b in peritoneal foam cells in order to identify regulated pathways. Material and Methods: A myeloid deficient Kdm6b mice (LysMCre-Kdm6b fl/fl ) was generated and bone marrow of Kdm6b wt or Kdm6b del mice was transplanted to irradiated Ldlr -/- mice which were fed a high fat diet for 9 weeks to induce foam cell formation. Peritoneal foam cells from Kdm6b del or Kdm6b wt mice were isolated and used for RNA-sequencing analysis. Results: Among the list of downregulated genes many genes involving fibrosis were affected in Kdm6b deficient foam cells including Collagen genes ( Col1a1 , Col1a2 ), Alpha smooth muscle actin ( Acta2 ) and Fibronectin-1 ( Fn1 ). Pathway analysis on downregulated genes ( P -value < 0.05) indicated that pathways involved in epithelial to mesenchymaltransition (EMT) ( q- value=10 -13 ) and extracellular matrix organization ( q- value=10 -4 ) were significantly downregulated. Pro-fibrotic pathways were thus strongly suppressed in Kdm6b deleted foam cells. Analysis of published datasets of foam cells showed that foam cell formation induces these pro-fibrotic characteristics. Overlay of both data sets indicated that fibrotic genes which are induced upon foam cell formation, are reduced in the absence of Kdm6b. These data suggest that foam cell formation induces a pro-fibrotic gene signature in a Kdm6b-dependent manner. Conclusion: We identified Kdm6b as a novel regulator of the pro-fibrotic signature of peritoneal foam cells.

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Signaling Pathways and Key Genes Involved in Regulation of foam Cell Formation in Atherosclerosis

Cells ◽

10.3390/cells9030584 ◽

2020 ◽

Vol 9 (3) ◽

pp. 584 ◽

Cited By ~ 16

Author(s):

Anastasia V. Poznyak ◽

Wei-Kai Wu ◽

Alexandra A. Melnichenko ◽

Reinhard Wetzker ◽

Vasily Sukhorukov ◽

...

Keyword(s):

Foam Cell ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cells ◽

Foam Cell Formation ◽

Beneficial Effects ◽

Complex Process ◽

Experimental Therapies ◽

Inflammatory Drugs

Atherosclerosis is associated with acute cardiovascular conditions, such as ischemic heart disease, myocardial infarction, and stroke, and is the leading cause of morbidity and mortality worldwide. Our understanding of atherosclerosis and the processes triggering its initiation is constantly improving, and, during the last few decades, many pathological processes related to this disease have been investigated in detail. For example, atherosclerosis has been considered to be a chronic inflammation triggered by the injury of the arterial wall. However, recent works showed that atherogenesis is a more complex process involving not only the immune system, but also resident cells of the vessel wall, genetic factors, altered hemodynamics, and changes in lipid metabolism. In this review, we focus on foam cells that are crucial for atherosclerosis lesion formation. It has been demonstrated that the formation of foam cells is induced by modified low-density lipoprotein (LDL). The beneficial effects of the majority of therapeutic strategies with generalized action, such as the use of anti-inflammatory drugs or antioxidants, were not confirmed by clinical studies. However, the experimental therapies targeting certain stages of atherosclerosis, among which are lipid accumulation, were shown to be more effective. This emphasizes the relevance of future detailed investigation of atherogenesis and the importance of new therapies development.

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