The Anti-Atherogenic Properties of Sesamin are Mediated via Improved Macrophage Cholesterol Efflux Through PPARγ1-LXRα and MAPK Signaling

2014 ◽  
Vol 84 (1-2) ◽  
pp. 79-91 ◽  
Author(s):  
Amin F. Majdalawieh ◽  
Hyo-Sung Ro
Keyword(s):  
Cholesterol Efflux ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Mapk Signaling ◽  
Luciferase Reporter ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Macrophage Cholesterol Efflux

Background: Foam cell formation resulting from disrupted macrophage cholesterol efflux, which is triggered by PPARγ1 and LXRα, is a hallmark of atherosclerosis. Sesamin and sesame oil exert anti-atherogenic effects in vivo. However, the exact molecular mechanisms underlying such effects are not fully understood. Aim: This study examines the potential effects of sesamin (0, 25, 50, 75, 100 μM) on PPARγ1 and LXRα expression and transcriptional activity as well as macrophage cholesterol efflux. Methods: PPARγ1 and LXRα expression and transcriptional activity are assessed by luciferase reporter assays. Macrophage cholesterol efflux is evaluated by ApoAI-specific cholesterol efflux assays. Results: The 50 μM, 75 μM, and 100 μM concentrations of sesamin up-regulated the expression of PPARγ1 (p< 0.001, p < 0.001, p < 0.001, respectively) and LXRα (p = 0.002, p < 0.001, p < 0.001, respectively) in a concentration-dependent manner. Moreover, 75 μM and 100 μM concentrations of sesamin led to 5.2-fold (p < 0.001) and 6.0-fold (p<0.001) increases in PPAR transcriptional activity and 3.9-fold (p< 0.001) and 4.2-fold (p < 0.001) increases in LXR transcriptional activity, respectively, in a concentration- and time-dependent manner via MAPK signaling. Consistently, 50 μM, 75 μM, and 100 μM concentrations of sesamin improved macrophage cholesterol efflux by 2.7-fold (p < 0.001), 4.2-fold (p < 0.001), and 4.2-fold (p < 0.001), respectively, via MAPK signaling. Conclusion: Our findings shed light on the molecular mechanism(s) underlying sesamin’s anti-atherogenic effects, which seem to be due, at least in part, to its ability to up-regulate PPARγ1 and LXRα expression and transcriptional activity, improving macrophage cholesterol efflux. We anticipate that sesamin may be used as a therapeutic agent for treating atherosclerosis.

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

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.

scholarly journals Atheroprotective action of a modified organoselenium compound: in vitro evidence

2016 ◽  
Vol 88 (3 suppl) ◽  
pp. 1953-1965 ◽  
Author(s):  
JADE DE OLIVEIRA ◽  
MARCOS R. STRALIOTTO ◽  
GIANNI MANCINI ◽  
CLAUDIA P. FIGUEIREDO ◽  
ANTÔNIO L. BRAGA ◽  
...  
Keyword(s):  
Foam Cell ◽  
Oxidized Ldl ◽  
Ldl Oxidation ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Protective Effects ◽  
Organoselenium Compound ◽  
Organoselenium Compounds ◽  
Concentration Dependent Manner

ABSTRACT Oxidation of low-density lipoprotein (LDL) has been strongly suggested to play a significant role in the pathogenesis of atherosclerosis. Thus, reducing LDL oxidation is a potential approach to decrease the risk of the atherosclerosis. Organoselenium compounds have demonstrated promising atheroprotective properties in experimental models. Herein, we tested the in vitro atheroprotective capability of a modified organoselenium compound, Compound HBD, in protecting isolated LDL from oxidation as well as foam cells formation. Moreover, the glutathione peroxidase (GPx)-like activity of Compound HBD was analyzed in order to explore the mechanisms related to the above-mentioned protective effects. The Compound HBD in a concentration-dependent manner reduced the Cu2+-induced formation of conjugated dienes. The protein portion from LDL were also protected from Cu2+-induced oxidation. Furthermore, the Compound HBD efficiently decreased the foam cell formation in J774 macrophage cells exposed to oxidized LDL. We found that the atheroprotective effects of this compound can be, at least in part, related to its GPx-like activity. Our findings demonstrated an impressive effect of Compound HBD against LDL-induced toxicity, a further in vivo study to investigate in more detail the antioxidant and antiatherogenic effects of this compound could be considered.

Abstract 168: The Acceleration of Foam Cell Formation by Chlamydia Pneumoniae Requires Nlrp3 Inflammasome Activation and Il-1 Signaling

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Gantsetseg Tumurkhuu ◽  
Jargalsaikhan Dagvadorj ◽  
Timothy R Crother ◽  
Kenichi Shimada ◽  
Moshe Arditi ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cholesterol Efflux ◽  
Molecular Mechanisms ◽  
Chlamydia Pneumoniae ◽  
Foam Cell ◽  
Cell Formation ◽  
Peritoneal Macrophages ◽  
Foam Cell Formation ◽  
Inflammasome Activation ◽  
Abca1 Expression

Background & Objective: Foam cell formation (FCF) due to excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis. Chlamydia pneumoniae (Cp) promotes FCF in the presence of oxLDL, but the exact molecular mechanisms are still not completely delineated. Recent data indicates that the Nlrp3 inflammasome plays an important role in the formation of atherosclerotic plaques. Here we investigated the role of the Nlrp3 inflammasome during the acceleration of FCF by Cp infection. Methods and Results: In order to determine if the NLRP3 inflammasome played a role in Cp infection induced acceleration of FCF, we treated resident peritoneal macrophages exposed to oxLDL and Cp with the IL-1R antagonist, Anakinra, to block IL-1 signaling. Treatment with Anakinra resulted in a significant reduction in FCF. Nlrp3-/-, Casp1-/-, and WT macrophages were also treated with live Cp in the presence or absence of oxLDL. We found that Nlrp3-/- and Casp1-/- macrophages had significantly less FCF compared with WT cells. Interestingly, both ABCA1 (cholesterol efflux transporter) and its transcription factor, liver X receptor (LXR-α), were increased in Nlrp3-/- and Casp1-/- macrophages compared with WT cells. Addition of rIL-1β to Nlrp3-/- macrophages led to a decrease in ABCA1 expression and greater FCF. Importantly, Il1r-/- macrophages also had greater ABCA1 expression and reduced FCF when exposed to oxLDL and Cp infection. Conclusion: These data suggest that Cp infection facilitates foam cell formation in the presence of oxLDL by producing NLRP3 dependent IL-1 cytokines, which then feed back on the macrophages and interferes with cholesterol efflux by negatively regulating ABCA1. In the absence of IL-1 signaling, the expression of ABCA1 is upregulated leading to greater cholesterol efflux and reduced FCF. Thus we have identified a novel regulatory loop controlling FCF. Understanding these interacting pathways will lead to new therapeutic strategies against atherosclerosis.

Abstract 42: Control of Macrophage Cholesterol Efflux and Atherogenesis by the Noncoding RNA MeXis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Tamer Sallam ◽  
Marius Jones ◽  
Brandon J Thomas ◽  
Xiaohui Wu ◽  
Thomas Gilliland ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Noncoding Rna ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Therapeutic Approaches ◽  
Chromosome Architecture ◽  
Expression Of Genes ◽  
Macrophage Cholesterol Efflux

The ligand-dependent nuclear receptor LXR regulates the expression of genes involved in responses to excess cholesterol including Abca1. Macrophage-specific cholesterol efflux driven by Abca1 has been causally linked to the prevention and reversal of heart disease, but therapeutic strategies for targeting efflux pathways in macrophages have been elusive. Here, we define a novel regulatory axis controlling macrophage responses to cholesterol overload. We identify the lncRNA MeXis as an amplifier of LXR-dependent Abca1 gene transcription in macrophages. MeXis interacts with and guides the promoter binding of nuclear receptor transcriptional coactivators. Loss of MeXis in murine immune cells has a marked impact on chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Our findings identify MeXis as a transcriptional gatekeeper that modifies the actions of LXR in lipid-dependent control of macrophage gene expression. It is conceivable that therapeutic approaches that enhance MeXis activity might augment reverse cholesterol transport and reduce foam cell formation.

scholarly journals Retinoic acid induces macrophage cholesterol efflux and inhibits atherosclerotic plaque formation in apoE-deficient mice

2015 ◽  
Vol 114 (4) ◽  
pp. 509-518 ◽  
Author(s):  
Wenjing Zhou ◽  
Jiacheng Lin ◽  
Hongen Chen ◽  
Jingjing Wang ◽  
Yan Liu ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Protein Expression ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Peritoneal Macrophages ◽  
Foam Cell Formation ◽  
Control Group ◽  
Dependent Manner ◽  
Dose Dependent

It has been suggested that retinoic acid (RA) has a potential role in the prevention of atherosclerotic CVD. In the present study, we used J774A.1 cell lines and primary peritoneal macrophages to investigate the protective effects of RA on foam cell formation and atherogenesis in apoE-deficient (apoE− / −) mice. A total of twenty male apoE− / − mice (n 10 animals per group), aged 8 weeks, were fed on a high-fat diet (HFD) and treated with vehicle or 9-cis-RA for 8 weeks. The atherosclerotic plaque area in the aortic sinus of mice in the 9-cis-RA group was 40·7 % less than that of mice in the control group (P< 0·01). Mouse peritoneal macrophages from the 9-cis-RA group had higher protein expression levels of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) than those from the control group. Serum total and LDL-cholesterol concentrations were lower in the 9-cis-RA group than in the control group (P< 0·05). In vitro studies showed that incubation of cholesterol-loaded J774A.1 macrophages with 9-cis-RA (0·1, 1 and 10 μmol/l) induced cholesterol efflux in a dose-dependent manner. The 9-cis-RA treatment markedly attenuated lipid accumulation in macrophages exposed to oxidised LDL. Moreover, treatment with 9-cis-RA significantly increased the protein expression levels of ABCA1 and ABCG1 in J774A.1 macrophages in a dose-dependent manner. Furthermore, 9-cis-RA dose-dependently enhanced the protein expression level of liver X receptor-α (LXRα), the upstream regulator of ABCA1 and ABCG1. Taken together, the present results show that 9-cis-RA suppresses foam cell formation and prevents HFD-induced atherogenesis via the LXRα-dependent up-regulation of ABCA1 and ABCG1.

scholarly journals Pharmacological Suppression of Hepcidin Increases Macrophage Cholesterol Efflux and Reduces Foam Cell Formation and Atherosclerosis

2012 ◽  
Vol 32 (2) ◽  
pp. 299-307 ◽  
Author(s):  
Omar Saeed ◽  
Fumiyuki Otsuka ◽  
Rohini Polavarapu ◽  
Vinit Karmali ◽  
Daiana Weiss ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Macrophage Cholesterol Efflux

scholarly journals Circular RNA hsa_circ_0006117 Facilitates Pancreatic Cancer Progression by Regulating the miR-96-5p/KRAS/MAPK Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Tao Liu ◽  
Lei Zhou ◽  
Zhiwei He ◽  
Yankun Chen ◽  
Xueyi Jiang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Circular Rna ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Molecular Characteristics ◽  
Dependent Manner

Circular RNAs (circRNAs) play key roles in many malignant tumors, including pancreatic cancer (PC); however, whether circular RNA hsa_circ_0006117, a newly identified circRNA, has a role in PC has not been investigated. Here, in order to elucidate the role and potential molecular mechanisms of circRNAs, we utilized bioinformatic tolls to screen the differentially expressed circRNAs in PC. Subsequently, circular RNA hsa_circ_0006117 was identified as being highly expressed in PC tissues in a screen of two GEO datasets, which was further verified in PC cell lines and tissues. Then, its molecular characteristics were investigated using methods such as Sanger sequencing and fluorescence in situ hybridization (FISH). Functional experiments subsequently indicated that circular RNA hsa_circ_0006117 facilitated the malignant behaviors of PC cells, prompting that it plays an oncogenic role in PC. Moreover, we found that circular RNA hsa_circ_0006117 exerts its PC-promoting effects via activating the KRAS/mitogen-activated protein kinase (MAPK) signaling pathway. Through bioinformatics exploration and dual-luciferase reporter assays, miR-96-5p was identified as a downstream target of circular RNA hsa_circ_0006117. A series of assays confirmed that circular RNA hsa_circ_0006117 acted as a miR-96-5p sponge, thereby promoting the malignant features of PC in a miR-96-5p/KRAS axis-dependent manner. Taken together, our study indicated, for the first time, that the specifically highly expressed circular RNA hsa_circ_0006117 facilitates PC progression via the modulation of the miR-96-5p/KRAS/MAPK signaling pathway and might be a hopeful therapeutic target for PC.

Abstract 451: HPODE Upregulates the Expression of Secretory Phospholipase A2 Group IIA in Rat Smooth Muscle Cells. Potential Contribution to the Progression of Atherosclerosis

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Zhaohui Yang ◽  
Chandrakala Aluganti Narasimhulu ◽  
Xueting Jiang ◽  
Sampath Parthasarathy
Keyword(s):  
Phospholipase A2 ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Foam Cell Formation ◽  
Potential Contribution ◽  
Dependent Manner ◽  
Secretory Phospholipase A2 ◽  
Concentration Dependent Manner ◽  
Decomposition Products ◽  
Secretory Phospholipase

Introduction Peroxidized lipids have been suggested to contribute to atherosclerosis in a number of ways. Accumulating evidence indicates that Group IIA secretory phospholipase A2 (sPLA2-IIA) may contribute to the atherogenic process and serve as markers for cardiovascular diseases. However, the relationship between lipid peroxides and sPLA2-IIA remain poorly identified. Hypothesis Peroxidized lipids such as HPODEs might induce the expression of sPLA2-IIA and enhance the uptake of LDL, thereby contributing to lipid accumulation. Methods Different concentrations of HPODE (0 μM, 12.5μM, 25μM) or oxidized -LDL (ox-LDL) (25μg/ml) were incubated with SMCs at 37°C. Real-time PCR was used to assay gene expression. The degradation of HPODE and ox-LDL was also monitored by the loss of peroxides and conjugated dienes. The formation of HPODE decomposition products was followed by electrospray mass spectrometry. Results Incubation of SMCs with HPODE resulted in an up-regulation of sPLA2-IIA mRNA expression in a concentration dependent manner. However, ox-LDL had limited or no effects in the expression of sPLA2. In addition, SMCs and peritoneal mouse macrophages pretreated with HPODE for 8hrs followed by DiI-LDL (20μg/ml) showed an increase in accumulation of labeled LDL as compared to control. We also noted that HPODE was decomposed by SMCs in hours as compared to no cell incubations. However, incubation of peroxidized lipids in the form of ox-LDL resulted in poor decomposition of the peroxides. Conclusion SMCs may break down the peroxidized fatty acids leading to the formation of simple compounds such as aldehydes and carboxylic acids. HPODE or its decomposition products may induce the expression of sPLA2-II and enhance foam cell formation.

scholarly journals Hesperetin inhibits foam cell formation in macrophages via activating LXRα signal in an AMPK dependent manner

2020 ◽  
Author(s):  
Xuanjing Chen ◽  
Dezhi Zou ◽  
Xiaoling Chen ◽  
Huanlin Wu ◽  
Danping Xu
Keyword(s):  
Protein Kinases ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Adenosine Monophosphate ◽  
Liver X Receptor ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Receptor Alpha ◽  
Liver X Receptor Alpha

AbstractCholesterol efflux from macrophages is the first step of cholesterol reverse transport (RCT), whose increase inhibits cholesterol accumulation and foam cell formation to suppress atherogenesis. Liver X receptor alpha (LXRα) and adenosine monophosphate activated protein kinases (AMPK) both have the pivotal role in cholesterol homeostasis. However the association between these two molecules in cell model of atherosclerosis is poorly understood. Hesperetin has been reported to possess several protective effects for cardiovascular diseases, while little is known about the role of hesperetin and its underlying mechanism on macrophage foam cell formation. In this study, we sought to investigate the potential effects of hesperetin in cholesterol efflux by using human macrophage derived foam cells, focusing on liver X receptor alpha (LXRα) and adenosine monophosphate activated protein kinases (AMPK) implication. Hesperetin treatment concentration-dependently reduced foam cell formation, intracellular cholesterol level and cholesterol esterification rate, and enhanced cholesterol efflux in THP-1 macrophages. Hesperetin upregulated the protein levels of LXRα and its targets including ABCA1, ABCG1 as well as SR-BI, and phosphorylated-AMPK. Meanwhile, hesperetin-induced upregulation of LXRα expression was enhanced by AMPK agonist and inhibited by AMPK inhibitor. Furthermore, hesperetin increased mRNA level of LXRα and its target genes, all which were depressed by AMPKα1/α2 small interfering RNA (siRNA) transfection. In conclusion, we founded for the first time that hesperetin could active AMPK. And this activation upregulated LXRα and its targets including ABCA1, ABCG1 and SR-BI, which significantly inhibited foam cell formation and promoted cholesterol efflux in THP-1 macrophages. Our results highlight the therapeutic potential of hespretin for the possible reduction in foam cell formation. This new mechanism could contribute the anti-atherogenic effects of hesperetin.

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