scholarly journals A Snake Venom-Secreted Phospholipase A2Induces Foam Cell Formation Depending on the Activation of Factors Involved in Lipid Homeostasis

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Elbio Leiguez ◽  
Karina Cristina Giannotti ◽  
Mariana do Nascimento Viana ◽  
Márcio Hideki Matsubara ◽  
Cristina Maria Fernandes ◽  
...  
Keyword(s):  
Protein Expression ◽  
Snake Venom ◽  
Foam Cell ◽  
Cell Formation ◽  
Lipid Homeostasis ◽  
Foam Cell Formation ◽  
Related Factors ◽  
Protein Levels ◽  
Inflammatory Processes ◽  
Functional Features

MT-III, a snake venom GIIA sPLA2, which shares structural and functional features with mammalian GIIA sPLA2s, activates macrophage defense functions including lipid droplet (LDs) formation, organelle involved in both lipid metabolism and inflammatory processes. Macrophages (MΦs) loaded with LDs, termed foam cells, characterize early blood vessel fatty-streak lesions during atherosclerosis. However, the factors involved in foam cell formation induced by a GIIA sPLA2are still unknown. Here, we investigated the participation of lipid homeostasis-related factors in LD formation induced by MT-III in macrophages. We found that MT-III activated PPAR-γand PPAR-β/δand increased the protein levels of both transcription factors and CD36 in macrophages. Pharmacological interventions evidenced that PPAR-γ, PPAR-β/δ, and CD36 as well as the endoplasmic reticulum enzymes ACAT and DGAT are essential for LD formation. Moreover, PPAR-β/δ, but not PPAR-γ, is involved in MT-III-induced PLIN2 protein expression, and both PPAR-β/δand PPAR-γupregulated CD36 protein expression, which contributes to MT-III-induced COX-2 expression. Furthermore, production of 15-d-PGJ2, an activator of PPARs, induced by MT-III, was dependent on COX-1 being LDs an important platform for generation of this mediator.

Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-β

2018 ◽  
Vol 132 (11) ◽  
pp. 1199-1213 ◽  
Author(s):  
Cheng Zhang ◽  
Juan-Juan Qin ◽  
Fu-Han Gong ◽  
Jing-Jing Tong ◽  
Wen-Lin Cheng ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Matrix Protein ◽  
Foam Cell ◽  
Cell Formation ◽  
Direct Interaction ◽  
Extracellular Matrix Protein ◽  
Mechanistic Study ◽  
Foam Cell Formation ◽  
Atheromatous Plaques ◽  
Inflammatory Processes

Mindin, which is a highly conserved extracellular matrix protein, has been documented to play pivotal roles in regulating angiogenesis, inflammatory processes, and immune responses. The aim of the present study was to assess whether mindin contributes to the development of atherosclerosis. A significant up-regulation of Mindin expression was observed in the serum, arteries and atheromatous plaques of ApoE−/− mice after high-fat diet treatment. Mindin−/−ApoE−/− mice and macrophage-specific mindin overexpression in ApoE−/− mice (Lyz2-mindin-TG) were generated to evaluate the effect of mindin on the development of atherosclerosis. The Mindin−/−ApoE−/− mice exhibited significantly ameliorated atherosclerotic burdens in the entire aorta and aortic root and increased atherosclerotic plaque stability. Moreover, bone marrow transplantation further demonstrated that mindin deficiency in macrophages was largely responsible for the alleviated atherogenesis. The Lyz2-mindin-TG mice exhibited the opposite phenotype. Mindin deficiency enhanced foam cell formation by increasing the expression of cholesterol effectors, including ABCA1 and ABCG1. The mechanistic study indicated that mindin ablation promoted LXR-β expression via a direct interaction. Importantly, LXR-β inhibition largely reversed the ameliorating effect of mindin deficiency on foam cell formation and ABCA1 and ABCG1 expression. The present study demonstrated that mindin deficiency serves as a novel mediator that protects against foam cell formation and atherosclerosis by directly interacting with LXR-β.

scholarly journals Role of pyruvate kinase M2 in oxidized LDL-induced macrophage foam cell formation and inflammation

2020 ◽  
Vol 61 (3) ◽  
pp. 351-364 ◽  
Author(s):  
Amit Kumar ◽  
Priya Gupta ◽  
Minakshi Rana ◽  
Tulika Chandra ◽  
Madhu Dikshit ◽  
...  
Keyword(s):  
Protein Expression ◽  
Pyruvate Kinase ◽  
Foam Cell ◽  
Aerobic Glycolysis ◽  
Oxidized Ldl ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Macrophage Foam Cell ◽  
Pyruvate Kinase M2

Pyruvate kinase M2 (PKM2) links metabolic and inflammatory dysfunction in atherosclerotic coronary artery disease; however, its role in oxidized LDL (Ox-LDL)-induced macrophage foam cell formation and inflammation is unknown and therefore was studied. In recombinant mouse granulocyte-macrophage colony-stimulating factor-differentiated murine bone marrow-derived macrophages, early (1–6 h) Ox-LDL treatment induced PKM2 tyrosine 105 phosphorylation and promotes its nuclear localization. PKM2 regulates aerobic glycolysis and inflammation because PKM2 shRNA or Shikonin abrogated Ox-LDL-induced hypoxia-inducible factor-1α target genes lactate dehydrogenase, glucose transporter member 1, interleukin 1β (IL-1β) mRNA expression, lactate, and secretory IL-1β production. PKM2 inhibition significantly increased Ox-LDL-induced ABCA1 and ABCG1 protein expression and NBD-cholesterol efflux to apoA1 and HDL. PKM2 shRNA significantly inhibited Ox-LDL-induced CD36, FASN protein expression, DiI-Ox-LDL binding and uptake, and cellular total cholesterol, free cholesterol, and cholesteryl ester content. Therefore, PKM2 regulates lipid uptake and efflux. DASA-58, a PKM2 activator, downregulated LXR-α, ABCA1, and ABCG1, and augmented FASN and CD36 protein expression. Peritoneal macrophages showed similar results. Ox-LDL induced PKM2- SREBP-1 interaction and FASN expression in a PKM2-dependent manner. Therefore, this study suggests a role for PKM2 in Ox-LDL-induced aerobic glycolysis, inflammation, and macrophage foam cell formation.

Tamoxifen inhibits macrophage FABP4 expression through the combined effects of the GR and PPARγ pathways

2013 ◽  
Vol 454 (3) ◽  
pp. 467-477 ◽  
Author(s):  
Meixiu Jiang ◽  
Ling Zhang ◽  
Xingzhe Ma ◽  
Wenquan Hu ◽  
Yuanli Chen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Promoter Activity ◽  
Foam Cell ◽  
Regulatory Element ◽  
Cell Formation ◽  
Disease Process ◽  
Foam Cell Formation ◽  
Combined Effects ◽  
Macrophage Foam Cell ◽  
Fatty Acid Binding

Macrophage adipocyte fatty acid-binding protein (FABP4) plays an important role in foam cell formation and development of atherosclerosis. Tamoxifen inhibits this disease process. In the present study, we determined whether the anti-atherogenic property of tamoxifen was related to its inhibition of macrophage FABP4 expression. We initially observed that tamoxifen inhibited macrophage/foam cell formation, but the inhibition was attenuated when FABP4 expression was selectively inhibited by siRNA. We then observed that tamoxifen and 4-hydroxytamoxifen inhibited FABP4 protein expression in primary macrophages isolated from both the male and female wild-type mice, suggesting that the inhibition is sex-independent. Tamoxifen and 4-hydroxytamoxifen inhibited macrophage FABP4 protein expression induced either by activation of GR (glucocorticoid receptor) or PPARγ (peroxisome-proliferator-activated receptor γ). Associated with the decreased protein expression, Fabp4 mRNA expression and promoter activity were also inhibited by tamoxifen and 4-hydroxytamoxifen, indicating transcriptional regulation. Analysis of promoter activity and EMSA/ChIP assays indicated that tamoxifen and 4-hydroxytamoxifen activated the nGRE (negative glucocorticoid regulatory element), but inhibited the PPRE (PPARγ regulatory element) in the Fabp4 gene. In vivo, administration of tamoxifen to ApoE (apolipoprotein E)-deficient (apoE−/−) mice on a high-fat diet decreased FABP4 expression in macrophages and adipose tissues as well as circulating FABP4 levels. Tamoxifen also inhibited FABP4 protein expression by human blood monocyte-derived macrophages. Taken together, the results of the present study show that tamoxifen inhibited FABP4 expression through the combined effects of GR and PPARγ signalling pathways. Our findings suggest that the inhibition of macrophage FABP4 expression can be attributed to the anti-atherogenic properties of tamoxifen.

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 Iron Together with Lipid Downregulates Protein Levels of Ceruloplasmin in Macrophages Associated with Rapid Foam Cell Formation

2016 ◽  
Vol 23 (10) ◽  
pp. 1201-1211 ◽  
Author(s):  
Qi Wang ◽  
Jiajie Ji ◽  
Shuangying Hao ◽  
Meng Zhang ◽  
Kuanyu Li ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Protein Levels

Andrographolide Inhibits Oxidized LDL-Induced Cholesterol Accumulation and Foam Cell Formation in Macrophages

2018 ◽  
Vol 46 (01) ◽  
pp. 87-106 ◽  
Author(s):  
Hung-Chih Lin ◽  
Chong-Kuei Lii ◽  
Hui-Chun Chen ◽  
Ai-Hsuan Lin ◽  
Ya-Chen Yang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Cholesterol Accumulation ◽  
Macrophage Foam Cell ◽  
Macrophage Foam Cells ◽  
Mrna And Protein Expression ◽  
Anti Inflammatory

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.

scholarly journals Growth differentiation factor-15 regulates oxLDL-induced lipid homeostasis and autophagy in human macrophages

2018 ◽  
Author(s):  
Kathrin Ackermann ◽  
Gabriel A. Bonaterra ◽  
Ralf Kinscherf ◽  
Anja Schwarz
Keyword(s):  
Lipid Accumulation ◽  
Transforming Growth Factor ◽  
Foam Cell ◽  
Cell Formation ◽  
Transforming Growth Factor Β ◽  
Lipid Homeostasis ◽  
Foam Cell Formation ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

AbstractGrowth differentiation factor-15 (GDF-15), a divergent and distant member of the transforming growth factor-β superfamily, is suggested as a risk factor for cardiovascular diseases. Thus, we are interested to investigate the influence of GDF-15 in lipid homeostasis and autophagy in macrophages (MΦ) during foam cell formation. Our investigations represent the impairment of GDF-15 on modulators of autophagy and lipid homeostasis in PMA-differentiated human THP-1 MΦ. In this context, in vitro resulted GDF-15 silencing in a reduction of lipid accumulation, whereas the addition of recombinant (r)GDF-15 increased the lipid accumulation in human MΦ independent of oxidized (ox)LDL. Additionally, GDF-15 affected the expression of autophagy-relevant proteins (p62, Atg5 and Atg12/Atg5 protein complex) and the p62 accumulation in THP-1 MΦ. Hence, our data suggest that GDF-15 is involved in the regulation of the lipid homoeostasis of human MΦ by regulating autophagic processes.

Simvastatin inhibited oxLDL-induced proatherogenic effects through calpain-1–PPARγ–CD36 pathway

2016 ◽  
Vol 94 (12) ◽  
pp. 1336-1343 ◽  
Author(s):  
Xueyan Yang ◽  
Meihui Yin ◽  
Lan Yu ◽  
Meili Lu ◽  
Hongxin Wang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Foam Cell ◽  
Cell Formation ◽  
Cholesterol Content ◽  
Foam Cell Formation ◽  
Calpain Inhibitor ◽  
Peroxisome Proliferator ◽  
Macrophage Foam Cell ◽  
Pparγ Agonist ◽  
Tnf Α

We previously reported that simvastatin, an inhibitor of HMG-CoA reductase, inhibits atherosclerosis in rats. The present study was designed to investigate the effect of simvastatin on mouse peritoneal macrophage foam cell formation, the early feature of atherosclerosis, and explore its mechanisms. The results showed that simvastatin decreased cholesterol content and DiI–oxLDL (1,1′-didodecyl 3,3,3′,3′-indocarbocyanine perchlorate – oxidized low-density lipoprotein) uptake, reduced the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the medium, down-regulated the mRNA and protein expression of CD36 (a fatty acid receptor), and reduced the mRNA expressions of peroxisome proliferator-activated receptor gamma (PPARγ), TNF-α, and IL-6 in macrophages treated with oxLDL. However, PPARγ agonist troglitazone partly abolished the effects of simvastatin on foam cells. In addition, simvastatin reduced the protein expression of calpain-1, a Ca2+-sensitive cysteine protease, in oxLDL-treated macrophages. Furthermore, PD150606, a specific calpain inhibitor, reduced mRNA expressions of PPARγ and CD36 in macrophages treated with oxLDL. Combination of simvastatin and PD150606 had no further effect on mRNA expression of PPARγ and CD36 compared with either alone. However, over-expression of calpain-1 in macrophages partly reversed the simvastatin effects, including cell cholesterol content, mRNA expressions of PPARγ, and CD36. The results suggested that simvastatin inhibits foam cell formation of oxLDL-treated macrophages through a calpain-1–PPARγ–CD36 pathway.

Cross-talk between TLR4-MyD88-NF-κB and SCAP-SREBP2 pathways mediates macrophage foam cell formation

2013 ◽  
Vol 304 (6) ◽  
pp. H874-H884 ◽  
Author(s):  
Lung-Chih Li ◽  
Zac Varghese ◽  
John F. Moorhead ◽  
Chien-Te Lee ◽  
Jin-Bor Chen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cross Talk ◽  
Foam Cell ◽  
Cell Formation ◽  
Regulatory Elements ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Iκb Kinase ◽  
Gene And Protein Expression ◽  
The Cross

Myeloid differentiation factor 88 (MyD88) and NF-κB play central roles in mediating signal transduction of the Toll-like receptor (TLR) superfamily in human macrophages. The feedback regulation of LDL receptor (LDLR) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) are mediated by the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP)-SREBP2 pathway and are key regulatory elements for cholesterol homeostasis in human cells. This study was designed to investigate cross-talk between TLR4-MyD88-NF-κB and SCAP-SREBP2 pathways in macrophage foam cell formation. phorbol 12-myristate 13-acetate-activated THP-1 macrophages were transfected with negative control or MyD88 small interfering (si)RNA. Transfected cells were incubated with LPS in the absence or presence of LDL or IκB kinase (IKK) inhibitor (BMS-345541). Intracellular cholesterol content was assessed. mRNA and protein expression of LDLR, HMG-CoAR, SCAP, and SREBP2 were examined by real-time RT-PCR and Western blot analysis. Intracellular translocation of SCAP in the organelles was detected by immunofluorecence and confocal microscopy. We demonstrated that LPS-induced cholesterol accumulation was attenuated by applying siRNA against MyD88 in the absence or presence of LDL. LPS increased both gene and protein expression of LDLR and HMG-CoAR by increasing expression and abnormal translocation of SCAP from the endoplasmic reticulum to the Golgi. These effects were blocked by knockdown of MyD88 or blockade of IKK or by knockdown of SCAP, suggesting that the cross-talk between NF-κB and SCAP plays an important role in macrophage foam cell formation and that interfering with the cross-talk might be a potential approach in preventing LPS-induced macrophage foam cell formation.

Periodontal Pathogens Promote Foam Cell Formation by Blocking Lipid Efflux

2021 ◽  
pp. 002203452110088
Author(s):  
J.H. Rho ◽  
H.J. Kim ◽  
J.Y. Joo ◽  
J.Y. Lee ◽  
J.H. Lee ◽  
...  
Keyword(s):  
Foam Cell ◽  
Experimental Studies ◽  
Cell Formation ◽  
Foam Cells ◽  
Periodontal Pathogen ◽  
Lipid Homeostasis ◽  
Foam Cell Formation ◽  
Periodontal Pathogens ◽  
Oil Red O

Foam cells are one of the major cellular components of atherosclerotic plaques, within which the trace of periodontal pathogens has also been identified in recent studies. In line with these findings, the correlation between periodontitis and atherosclerotic cardiovascular incidences has been repetitively supported by evidence from a number of experimental studies. However, the direct role of periodontal pathogens in altered cellular signaling underlying such cardiovascular events has not been clearly defined. To determine the role of periodontal pathogens in the pathogenesis of atherosclerosis, especially in the evolution of macrophages into foam cells, we monitored the pattern of lipid accumulation within macrophages in the presence of periodontal pathogens, followed by characterization of these lipids and investigation of major molecules involved in lipid homeostasis. The cells were stained with the lipophilic fluorescent dye BODIPY 493/503 and Oil Red O to characterize the lipid profile. The amounts of Oil Red O–positive droplets, representing neutral lipids, as well as fluorescent lipid aggregates were prominently increased in periodontal pathogen–infected macrophages. Subsequent analysis allowed us to locate the accumulated lipids in the endoplasmic reticulum. In addition, the levels of cholesteryl ester in periodontal pathogen–infected macrophages were increased, implying disrupted lipid homeostasis. Further investigations to delineate the key messengers and regulatory factors involved in the altered lipid homeostasis have revealed alterations in cholesterol efflux–related enzymes, such as ABCG1 and CYP46A1, as contributors to foam cell formation, and increased Ca2+ signaling and reactive oxygen species (ROS) production as key events underlying disrupted lipid homeostasis. Consistently, a treatment of periodontal pathogen–infected macrophages with ROS inhibitors and nifedipine attenuated the accumulation of lipid droplets, further confirming periodontal pathogen–induced alterations in Ca2+ and ROS signaling and the subsequent dysregulation of lipid homeostasis as key regulatory events underlying the evolution of macrophages into foam cells.

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