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1.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802600

RESUMO

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.


Assuntos
Aterosclerose/metabolismo , Células Espumosas/metabolismo , RNA não Traduzido/metabolismo , Animais , Transporte Biológico/fisiologia , Colesterol/metabolismo , Citocinas/metabolismo , Humanos , Metabolismo dos Lipídeos/fisiologia
2.
Molecules ; 26(1)2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33401401

RESUMO

There is a high level of interest in identifying metabolites of endogenously produced or dietary compounds generated by the gastrointestinal (GI) tract microbiota, and determining the functions of these metabolites in health and disease. There is a wealth of compelling evidence that the microbiota is linked with many complex chronic inflammatory diseases, including atherosclerosis. Macrophages are key target immune cells in atherosclerosis. A hallmark of atherosclerosis is the accumulation of pro-inflammatory macrophages in coronary arteries that respond to pro-atherogenic stimuli and failure of digesting lipids that contribute to foam cell formation in atherosclerotic plaques. This review illustrates the role of tryptophan-derived microbiota metabolites as an aryl hydrocarbon receptor (AhR) ligand that has immunomodulatory properties. Also, microbiota-dependent trimethylamine-N-oxide (TMAO) metabolite production is associated with a deleterious effect that promotes atherosclerosis, and metabolite indoxyl sulfate has been shown to exacerbate atherosclerosis. Our objective in this review is to discuss the role of microbiota-derived metabolites in atherosclerosis, specifically the consequences of microbiota-induced effects of innate immunity in response to atherogenic stimuli, and how specific beneficial/detrimental metabolites impact the development of atherosclerosis by regulating chronic endotoxemic and lipotoxic inflammation.


Assuntos
Aterosclerose , Células Espumosas , Microbioma Gastrointestinal/imunologia , Indicã , Metilaminas , Animais , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/microbiologia , Aterosclerose/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Espumosas/imunologia , Células Espumosas/metabolismo , Células Espumosas/patologia , Humanos , Indicã/imunologia , Indicã/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Metilaminas/imunologia , Metilaminas/metabolismo , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo
3.
Arterioscler Thromb Vasc Biol ; 41(3): 1076-1091, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33504177

RESUMO

OBJECTIVE: Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfate N-acetylgalactosaminyltransferase-2), in macrophage foam cell formation. Approach and Results: ChGn-2-deficient mice showed decreased and shortened glycosaminoglycans. ChGn-2-/-/LDLr-/- (low-density lipoprotein receptor) mice generated less atherosclerotic plaque after being fed with Western diet despite exhibiting a metabolic phenotype similar to that of the ChGn-2+/+/LDLr-/- littermates. We demonstrated that in macrophages, ChGn-2 expression was upregulated in the presence of oxLDL (oxidized LDL), and glycosaminoglycan was substantially increased. Foam cell formation was significantly altered by ChGn-2 in both mouse peritoneal macrophages and the RAW264.7 macrophage cell line. Mechanistically, ChGn-2 enhanced oxLDL binding on the cell surface, and as a consequence, CD36-an important macrophage membrane scavenger receptor-was differentially regulated. CONCLUSIONS: ChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Aterosclerose/metabolismo , Células Espumosas/metabolismo , Glicosaminoglicanos/metabolismo , N-Acetilgalactosaminiltransferases/metabolismo , Animais , Aterosclerose/etiologia , Aterosclerose/patologia , Modelos Animais de Doenças , Feminino , Células Espumosas/patologia , Glicosaminoglicanos/química , Lipoproteínas LDL/metabolismo , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Acetilgalactosaminiltransferases/deficiência , N-Acetilgalactosaminiltransferases/genética , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Células RAW 264.7 , Regulação para Cima
4.
J Thromb Haemost ; 19(4): 941-953, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33492784

RESUMO

OBJECTIVE: Plasminogen/plasmin is a serine protease system primarily responsible for degrading fibrin within blood clots. Plasminogen mediates its functions by interacting with plasminogen receptors on the cell surface. H2B, one such plasminogen receptor, is found on the surface of several cell types including macrophages. Both basic and clinical studies support the role of plasminogen in the process of foam cell formation (FCF), a hallmark of atherosclerosis. Growing evidence also implicates serine protease-activated receptors (PARs) in atherosclerosis. These receptors are also found on macrophages, and plasmin is capable of activating PAR1 and PAR4. The goal of this study was to determine the extent of H2B's contribution to plasminogen-mediated FCF by macrophages and if PARs are involved in this process. APPROACH AND RESULTS: Treating macrophages with plasminogen increases their oxidized low-density lipoprotein uptake and plasminogen-mediated foam cell formation (Plg-FCF) significantly. The magnitude of Plg-FCF correlates with cell-surface expression of the H2B level. H2B blockade or downregulation reduces Plg-FCF, whereas its overexpression or high endogenous levels increases Plg-FCF. Modulating PAR1 level in mouse macrophages affects Plg-FCF. Activation/overexpression of PAR1 increases and its blockade/knockdown reduces this response. Confocal imaging indicates that both H2B and PAR1 colocalize with clathrin coated pits on the surface of macrophages, and reducing expression of clathrin or interfering with the clathrin-coated pits integrity reduces Plg-FCF. CONCLUSION: Our data indicate that the magnitude of Plg-FCF by macrophages is proportional to the H2B levels and demonstrate for the first time that PAR1 is involved in this process and that the integrity of clathrin-coated pits is required for the full effect of Plg-induced FCF.


Assuntos
Células Espumosas , Plasminogênio , Animais , Clatrina/metabolismo , Fibrinolisina/metabolismo , Células Espumosas/metabolismo , Histonas , Macrófagos/metabolismo , Camundongos , Plasminogênio/metabolismo , Receptor PAR-1
5.
Exp Mol Pathol ; 118: 104604, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33434610

RESUMO

INTRODUCTION AND AIMS: Oxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. METHODS: THP-1 differentiated macrophages were treated with media, LPS (100 ng/ml), LPS + OT (10 pM), or LPS + OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while oxLDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. RESULTS: RT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OT + LPS treatment, compared to LPS alone (p = 0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of oxLDL uptake showed a significantly lower fluorescent value in LPS + OT (100pM) -treated cells when compared to LPS alone (p < 0.0001). While not statistically significant (p = 0.06), cholesterol efflux capacity increased with LPS + OT treatment. CONCLUSION: We demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.


Assuntos
Aterosclerose/tratamento farmacológico , Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Ocitocina/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Células Espumosas/metabolismo , Células Espumosas/patologia , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Macrófagos/patologia , Ocitócicos/farmacologia , Placa Aterosclerótica/induzido quimicamente , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Receptores de Ocitocina/metabolismo
6.
Nat Commun ; 11(1): 5426, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110060

RESUMO

Novel atherosclerosis models are needed to guide clinical therapy. Here, we report an in vitro model of early atherosclerosis by fabricating and perfusing multi-layer arteriole-scale human tissue-engineered blood vessels (TEBVs) by plastic compression. TEBVs maintain mechanical strength, vasoactivity, and nitric oxide (NO) production for at least 4 weeks. Perfusion of TEBVs at a physiological shear stress with enzyme-modified low-density-lipoprotein (eLDL) with or without TNFα promotes monocyte accumulation, reduces vasoactivity, alters NO production, which leads to endothelial cell activation, monocyte accumulation, foam cell formation and expression of pro-inflammatory cytokines. Removing eLDL leads to recovery of vasoactivity, but not loss of foam cells or recovery of permeability, while pretreatment with lovastatin or the P2Y11 inhibitor NF157 reduces monocyte accumulation and blocks foam cell formation. Perfusion with blood leads to increased monocyte adhesion. This atherosclerosis model can identify the role of drugs on specific vascular functions that cannot be assessed in vivo.


Assuntos
Arteríolas/fisiopatologia , Aterosclerose/fisiopatologia , Arteríolas/química , Arteríolas/citologia , Aterosclerose/genética , Aterosclerose/metabolismo , Fenômenos Biomecânicos , Adesão Celular , Proliferação de Células , Células Cultivadas , Células Espumosas/citologia , Células Espumosas/metabolismo , Humanos , Lipoproteínas LDL/metabolismo , Modelos Biológicos , Monócitos/citologia , Monócitos/metabolismo , Óxido Nítrico/metabolismo , Engenharia Tecidual , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
7.
Am J Physiol Heart Circ Physiol ; 319(4): H835-H846, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795179

RESUMO

Analyses of individual atherosclerotic plaques are mostly descriptive, relying, for example, on histological classification by spectral analysis of ultrasound waves or staining and observing particular cellular components. Such passive methods have proved useful for characterizing the structure and vulnerability of plaques but have little quantitative predictive power. Our aim is to introduce and discuss a computational framework to provide insight to clinicians and help them visualize internal plaque dynamics. We use partial differential equations (PDEs) with macrophages, necrotic cells, oxidized lipids, oxygen concentration, and platelet-derived growth factor (PDGF) as primary variables coupled to a biomechanical model to describe vessel growth. The model is deterministic, providing mechanical, morphological, and histological characteristics of an atherosclerotic vessel at any desired future time point. We use our model to create computer-generated animations of a plaque evolution that are in qualitative agreement with published serial ultrasound images and hypothesize possible atherogenic mechanisms. A systems biology model consisting of five differential equations is able to capture the morphology of necrotic cores residing within vulnerable atherosclerotic plaque. In the context of the model, the distribution of oxidized low-density lipoprotein (Ox-LDL) particles, endothelial inflammation, plaque oxygenation (via the presence of vasa vasora), and intimal oxygenation are four important factors that drive changes in core morphology.NEW & NOTEWORTHY In this article, we propose a quantitative framework to describe the evolution of atherosclerotic plaque. We use partial differential equations (PDEs) with macrophages, necrotic cells, oxidized lipids, oxygen concentration, and PDGF as primary variables coupled to a biomechanical model to describe vessel growth. A feature of our method is that it outputs color-coded vessel sections corresponding to regions of the plaque that are necrotic and fibrous, qualitatively similar to images generated by enhanced intravascular ultrasound.


Assuntos
Artérias/patologia , Aterosclerose/patologia , Simulação por Computador , Modelos Cardiovasculares , Placa Aterosclerótica , Biologia de Sistemas , Animais , Artérias/metabolismo , Aterosclerose/metabolismo , Difusão , Progressão da Doença , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Espumosas/metabolismo , Células Espumosas/patologia , Humanos , Mediadores da Inflamação/metabolismo , Lipoproteínas LDL/metabolismo , Necrose , Oxigênio/metabolismo
8.
Nutr Metab Cardiovasc Dis ; 30(9): 1590-1599, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32605883

RESUMO

BACKGROUND AND AIMS: Hypercholesterolemia and oxidative stress are two of the most important risk factors for atherosclerosis. The aim of the present work was to evaluate mandarin (Citrus reticulata) peel oil (MPO) in cholesterol metabolism and lipid synthesis, and its antioxidant capacity. METHODS AND RESULTS: Incubation of hepatic HepG2 cells with MPO (15-60 µL/L) reduced cholesterogenesis and saponifiable lipid synthesis, demonstrated by [14C]acetate radioactivity assays. These effects were associated with a decrease in a post-squalene reaction of the mevalonate pathway. Molecular docking analyses were carried out using three different scoring functions to examine the cholesterol-lowering property of all the components of MPO against lanosterol synthase. Docking simulations proposed that minor components of MPO monoterpenes, like alpha-farnesene and neryl acetate, as well the major component, limonene and its metabolites, could be partly responsible for the inhibitory effects observed in culture assays. MPO also decreased RAW 264.7 foam cell lipid storage and its CD36 expression, and prevented low-density lipoprotein (LDL) lipid peroxidation. CONCLUSION: These results may imply a potential role of MPO in preventing atherosclerosis by a mechanism involving inhibition of lipid synthesis and storage and the decrease of LDL lipid peroxidation.


Assuntos
Antioxidantes/farmacologia , Aterosclerose/prevenção & controle , Colesterol/metabolismo , Citrus , Dislipidemias/tratamento farmacológico , Células Espumosas/efeitos dos fármacos , Frutas , Hepatócitos/efeitos dos fármacos , Hipolipemiantes/farmacologia , Lipoproteínas LDL/metabolismo , Óleos Vegetais/farmacologia , Animais , Antioxidantes/isolamento & purificação , Aterosclerose/etiologia , Aterosclerose/metabolismo , Antígenos CD36/metabolismo , Citrus/química , Dislipidemias/complicações , Dislipidemias/metabolismo , Células Espumosas/metabolismo , Frutas/química , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Hipolipemiantes/isolamento & purificação , Transferases Intramoleculares/antagonistas & inibidores , Transferases Intramoleculares/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Óleos Vegetais/isolamento & purificação , Células RAW 264.7
9.
Proc Natl Acad Sci U S A ; 117(19): 10476-10483, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32354992

RESUMO

Cholesterol-laden macrophage foam cells are a hallmark of atherosclerosis. For that reason, cholesterol metabolism in macrophages has attracted considerable scrutiny, particularly the mechanisms by which macrophages unload surplus cholesterol (a process referred to as "cholesterol efflux"). Many studies of cholesterol efflux in macrophages have focused on the role of ABC transporters in moving cholesterol onto high-density lipoproteins (HDLs), but other mechanisms for cholesterol efflux likely exist. We hypothesized that macrophages have the capacity to unload cholesterol directly onto adjacent cells. To test this hypothesis, we used methyl-ß-cyclodextrin (MßCD) to load mouse peritoneal macrophages with [13C]cholesterol. We then plated the macrophages (in the absence of serum or HDL) onto smooth muscle cells (SMCs) that had been metabolically labeled with [15N]choline. After incubating the cells overnight in the absence of HDL or serum, we visualized 13C and 15N distribution by nanoscale secondary ion mass spectrometry (NanoSIMS). We observed substantial 13C enrichment in SMCs that were adjacent to [13C]cholesterol-loaded macrophages-including in cytosolic lipid droplets of SMCs. In follow-up studies, we depleted "accessible cholesterol" from the plasma membrane of [13C]cholesterol-loaded macrophages with MßCD before plating the macrophages onto the SMCs. After an overnight incubation, we again observed substantial 13C enrichment in the SMCs adjacent to macrophages. Thus, macrophages transfer cholesterol to adjacent cells in the absence of serum or HDL. We suspect that macrophages within tissues transfer cholesterol to adjacent cells, thereby contributing to the ability to unload surplus cholesterol.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Macrófagos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/fisiologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Transporte Biológico , Células Espumosas/metabolismo , Metabolismo dos Lipídeos , Lipoproteínas HDL/metabolismo , Macrófagos/fisiologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Soro/metabolismo , beta-Ciclodextrinas/metabolismo
10.
BMC Cardiovasc Disord ; 20(1): 211, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375652

RESUMO

BACKGROUND: Lipid infiltration and inflammatory response run through the occurrence of atherosclerosis. Differentiation into macrophages and foam cell formation are the key steps of AS. Aim of this study was that the differential gene expression between foam cells and macrophages was analyzed to search the key links of foam cell generation, so as to explore the pathogenesis of atherosclerosis and provide targets for the early screening and prevention of coronary artery disease (CAD). METHODS: The gene expression profiles of GSE9874 were downloaded from Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE9874) on GPL96 [HG-U133A] Affymetrix Human Genome U133. A total of 22,383 genes were analyzed for differentially expression genes (DEGs) by Bayes package. GO enrichment analysis and KEGG pathway analysis for DEGs were performed using KOBAS 3.0 software (Peking University, Beijing, China). STRING software (STRING 10.0; European Molecular Biology Laboratory, Heidelberg, Germany) was used to analyze the protein-protein interaction (PPI) of DEGs. RESULTS: A total of 167 DEGs between macrophages and foam cells were identified. Compared with macrophages, 102 genes were significantly upregulated and 65 genes were significantly downregulated (P < 0.01, fold-change > 1) in foam cells. DEGs were mainly enrich in 'sterol biosynthetic and metabolic process', 'cholesterol metabolic and biosynthetic process' by GO enrichment analysis. The results of KEGG pathway analysis showed all differential genes are involved in biological processes through 143 KEGG pathways. A PPI network of the DEGs was constructed and 10 outstanding genes of the PPI network was identified by using Cytoscape, which include HMGCR, SREBF2, LDLR, HMGCS1, FDFT1, LPL, DHCR24, SQLE, ABCA1 and FDPS. CONCLUSION: Lipid metabolism related genes and molecular pathways were the key to the transformation of macrophages into foam cells. Therefore, lipid metabolism disorder is the key to turn macrophages into foam cells, which plays a major role in CAD.


Assuntos
Aterosclerose/genética , Células Espumosas/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Análise de Sequência com Séries de Oligonucleotídeos , Mapas de Interação de Proteínas , Transdução de Sinais/genética , Transcriptoma , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Bases de Dados Genéticas , Células Espumosas/patologia , Humanos
11.
Vascul Pharmacol ; 128-129: 106675, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32200116

RESUMO

The transformation of macrophages to foam cells is a critical component in atherosclerotic lesion formation. Maslinic acid (MA), a novel natural pentacyclic triterpene, has cardioprotective and anti-inflammatory properties. It is hypothesized that MA can suppress monocyte recruitment to endothelial cells and inhibit macrophage foam cells formation. Previous study shows that MA inhibits inflammatory effects induced by sPLA2-IIA, including foam cells formation. This study elucidates the regulatory effect of MA in monocyte recruitment, macrophage lipid accumulation and cholesterol efflux. Our findings demonstrate that MA inhibits THP-1 monocyte adhesion to HUVEC cells in a TNFα-dependent and independent manner, but it induces trans-endothelial migration marginally at low concentration. MA down-regulates both gene and protein expression on VCAM-1 and MCP-1 in HUVECs. We further showed that MA suppresses macrophage foam cells formation, as indicated from the Oil-Red-O staining and flow cytometric analysis of intracellular lipids accumulation. The effects observed may be attributed to the antioxidant properties of MA where it was shown to suppress CuSO4-induced lipid peroxidation. MA inhibits scavenger receptors SR-A and CD36 expression while enhancing cholesterol efflux. MA enhances cholesterol efflux transporters ABCA1 and ABCG1 genes expression marginally without inducing its protein expression. In this study, MA was shown to target important steps that contribute to foam cell formation, including its ability in reducing monocytes adhesion to endothelial cells and LDL peroxidation, down-regulating scavenger receptors expression as well as enhancing cholesterol efflux, which might be of great importance in the context of atherosclerosis prevention and treatment.


Assuntos
Antioxidantes/farmacologia , Aterosclerose/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Triterpenos/farmacologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Células Espumosas/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Monócitos/metabolismo , Células THP-1 , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
12.
BMC Cardiovasc Disord ; 20(1): 120, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32138681

RESUMO

BACKGROUND: Atherosclerosis (AS) is the basis of cardiovascular diseases, characterized by chronic inflammatory and lipid metabolism disorders. Although the anti-inflammatory effect of Klotho in AS has been clearly shown, its lipid-lowering effect is unclear. In this study, we examined the effects of recombinant Klotho (Re-KL) protein on lipid accumulation in foam cells. METHODS: THP-1 cells were exposed to 100 nM phorbol myristate acetate for 24 h and then to oxidized low-density lipoprotein (ox-LDL; 80 mg/mL) to induce foam cell formation. Subsequently, the foam cells were incubated with Re-KL and/or DKK1, an inhibitor of the Wnt/ß-catenin pathway. RESULTS: Oil red O staining and cholesterol intake assay revealed that the foam cell model was constructed successfully. Pre-treatment of the foam cells with Re-KL decreased total cholesterol level, up-regulated the expression of ATP binding cassette transporter A1 (ABCA1) and G1 (ABCG1), and down-regulated the expression of acyl coenzyme a-cholesterol acyltransferase 1 (ACAT1) and members of the scavenger family (SR-A1 and CD36). In addition, the expression of Wnt/ß-catenin pathway-related proteins in foam cells was significantly decreased by the stimulus of Re-KL. Interestingly, the effect of Re-KL was similar to that of DKK1 on foam cells. CONCLUSIONS: The Re-KL-induced up-regulation of reverse cholesterol transport capacity promotes cholesterol efflux and reduces lipid accumulation by suppressing the Wnt/ß-catenin pathway in foam cells.


Assuntos
Anticolesterolemiantes/farmacologia , Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Glucuronidase/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Transporte Biológico , Células Espumosas/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Lipoproteínas LDL/farmacologia , Proteínas Recombinantes/farmacologia , Células THP-1
13.
J Immunol Res ; 2020: 5284728, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149158

RESUMO

Atherosclerosis is a multifactorial chronic inflammatory arterial disease forming the pathological basis of many cardiovascular diseases such as coronary heart disease, heart failure, and stroke. Numerous studies have implicated inflammation as a key player in the initiation and progression of atherosclerosis. Galectin-3 (Gal-3) is a 30 kDa ß-galactose, highly conserved and widely distributed intracellularly and extracellularly. Gal-3 has been demonstrated in recent years to be a novel inflammatory factor participating in the process of intravascular inflammation, lipid endocytosis, macrophage activation, cellular proliferation, monocyte chemotaxis, and cell adhesion. This review focuses on the role of Gal-3 in atherosclerosis and the mechanism involved and several classical Gal-3 agonists and antagonists in the current studies.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Suscetibilidade a Doenças , Galectina 3/metabolismo , Animais , Aterosclerose/epidemiologia , Aterosclerose/patologia , Biomarcadores , Modelos Animais de Doenças , Endotélio/metabolismo , Células Espumosas/imunologia , Células Espumosas/metabolismo , Células Espumosas/patologia , Galectina 3/química , Galectina 3/genética , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Estresse Oxidativo
14.
Biochemistry (Mosc) ; 85(Suppl 1): S34-S55, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32087053

RESUMO

This review discusses formation of reactive halogen species (RHS) catalyzed by myeloperoxidase (MPO), an enzyme mostly present in leukocytes. An imbalance between the RHS production and body's ability to remove or neutralize them leads to the development of halogenative stress. RHS reactions with proteins, lipids, carbohydrates, and antioxidants in the content of low-density lipoproteins (LDLs) of the human blood are described. MPO binds site-specifically to the LDL surface and modifies LDL properties and structural organization, which leads to the LDL conversion into proatherogenic forms captured by monocytes/macrophages, which causes accumulation of cholesterol and its esters in these cells and their transformation into foam cells, the basis of atherosclerotic plaques. The review describes the biomarkers of MPO enzymatic activity and halogenative stress, as well as the involvement of the latter in the development of atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Halogenação , Halogênios/metabolismo , Lipoproteínas LDL/metabolismo , Placa Aterosclerótica/metabolismo , Sítios de Ligação , Biomarcadores/metabolismo , Colesterol/metabolismo , Ácidos Graxos Insaturados/metabolismo , Células Espumosas/metabolismo , Radicais Livres/metabolismo , Humanos , Ácido Hipocloroso/metabolismo , Leucócitos/metabolismo , Peroxidase/metabolismo
15.
Chem Commun (Camb) ; 56(17): 2610-2613, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32016272

RESUMO

We have synthesized a turn-on fluorescent probe, termed NB4OH, to detect cellular hypochlorite. NB4OH is mainly localized in the endoplasmic reticulum and detects ClO- in foam cells. The fluorescence change of the probe was explained by theoretical calculation as a PET process. The probe holds great promise for application in biomedical research, including atherosclerosis research.


Assuntos
Aterosclerose/metabolismo , Retículo Endoplasmático/metabolismo , Células Espumosas/metabolismo , Ácido Hipocloroso/metabolismo , Sondas Moleculares/metabolismo , Humanos , Espectrometria de Fluorescência
16.
Int J Mol Sci ; 21(3)2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32012706

RESUMO

Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response.


Assuntos
Células Espumosas/metabolismo , Células Espumosas/patologia , Lipoproteínas LDL/metabolismo , Fagocitose , Biomarcadores , Células Espumosas/imunologia , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imunidade Inata , Metabolismo dos Lipídeos , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Oxirredução , Fagocitose/genética , Fagocitose/imunologia , Transdução de Sinais , Transcriptoma
17.
Gene ; 731: 144364, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31935511

RESUMO

Apolipoprotein C2 (ApoC2) is an important member of the apolipoprotein C family and functions as a major activator of lipoprotein lipase (LPL). In cardiovascular and cerebrovascular systems, the lipolytic activity of the LPL-ApoC2 complex is critical for the metabolism of triglyceride-rich lipoproteins and contributes to the pathogenesis of ischemic stroke (IS). However, the regulation of ApoC2 in IS development remains unclear. In this study, we first explored potential ApoC2-targeting microRNAs (miRNAs) by bioinformatics tool and compared the miRNA expression profiles in the blood cells of 25 IS patients and 25 control subjects by miRNA microarray. miR-1275 was predicted to bind with the 3' untranslated region of ApoC2, and a significant reduction of blood miR-1275 levels was observed in IS patients. Dual-luciferase reporter assay and quantitative RT-PCR confirmed the regulation of ApoC2 by miR-1275 in THP-1 derived macrophages. miR-1275 also inhibited cellular uptake of ox-LDL and suppressed formation of macrophage foam cell. Furthermore, the whole blood miR-1275 levels were validated in 279 IS patients and 279 control subjects by TaqMan assay. miR-1275 levels were significantly lower in IS cases and logistic regression analysis showed that miR-1275 level was negatively associated with the occurrence of IS (adjusted OR, 0.76; 95% CI, 0.69-0.85; p < 0.001). Addition of miR-1275 to traditional risk factors showed an additive prediction value for IS. Our study shows that blood miR-1275 levels were negatively associated with the occurrence of IS, and miR-1275 might exert an athero-protective role against the development of IS by targeting ApoC2 and blocking the formation of macrophage foam cells.


Assuntos
Apolipoproteína C-II/genética , Células Espumosas/patologia , MicroRNAs/sangue , Acidente Vascular Cerebral/genética , Apolipoproteína C-II/metabolismo , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Isquemia Encefálica/sangue , Isquemia Encefálica/complicações , Isquemia Encefálica/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Células Espumosas/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Macrófagos/patologia , Macrófagos/fisiologia , Masculino , MicroRNAs/fisiologia , Fatores de Risco , Acidente Vascular Cerebral/sangue , Células THP-1
18.
Int Heart J ; 61(1): 153-159, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31956131

RESUMO

A previous study and a gene-annotation enrichment analysis for potential targets of the microRNA miR-202-3p both suggest that this microRNA might be implicated in cardiovascular and metabolic diseases. In the present study, the role of miR-202-3p in the pathogenesis of coronary heart disease (CHD) was explored. We conduct a case-control study to detect the expression levels of miR-202-3p in peripheral blood cells and found that miR-202-3p expression was significantly higher in CHD cases than in controls (P < 0.001). miR-202-3p levels were negatively correlated with platelet distribution width (r = -0.348, P = 0.002) and mean platelet volume (r = -0.29, P = 0.01). Further functional analyses suggested that stimulation with oxidized low-density lipoprotein (ox-LDL) induced miR-202-3p expression, and that this microRNA suppressed the formation of ox-LDL-induced macrophage foam cells derived from THP-1 cells in a feedback manner. In addition, miR-202-3p overexpression modulated the expression of several key genes involved in foam cell formation, including that of ABCG4, NCEH1I, and SCARB2. In summary, miR-202-3p was associated with CHD, exerting a protective role against CHD by feedback suppression of ox-LDL-induced macrophage foam cell formation.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Doença das Coronárias/genética , Células Espumosas/citologia , MicroRNAs/genética , Idoso , Estudos de Casos e Controles , Células Cultivadas , Feminino , Células Espumosas/metabolismo , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lipoproteínas LDL/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Células THP-1 , Regulação para Cima
19.
Biochem Biophys Res Commun ; 524(1): 77-82, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-31980179

RESUMO

OBJECTIVES: Protein arginine methyltransferase 2 (PRMT2) is closely related to the occurrence and development of atherosclerosis. However, its underlying mechanisms remain to be elucidated. The purpose of this study is to observe the effect of overexpression of PRMT2 on the formation of foam cells and to explore its possible mechanism in RAW 264.7 macrophage. METHODS: Lentivirus vector of overexpression PRMT2 (LV-PRMT2) was constructed. LV-PRMT2 and lentivirus vector GV492 were transfected into RAW 264.7 macrophages, positive clone cells were screened by treatment with 4.0 µg/mL puromycin for 4 weeks. The macrophages were treated with ox-LDL (50 µg/mL) for 48 h to induce foaming. The lipid accumulation of macrophages was observed by oil red O staining. The levels of cellular total cholesterol (TC), free cholesterol (FC) and cholesteryl ester (CE) were measured by high performance liquid chromatography (HPLC) assays. The cholesterol efflux of macrophages was tested by the [3H] labeled cholesterol. The expressions of ATP binding cassette transporter A1 (ABCA1), ATP binding cassette transporter G1 (ABCG1), CD36 and scavenger receptor A1 (SR-A1) in macrophages were measured by Western Blot. RESULTS: The results showed that LV-PRMT2 and lentivirus vector has been successfully transfected into RAW 264.7 macrophage. Compared with the Vector group, the mRNA and protein expressions of PRMT2 were significantly up-regulated (P < 0.05). Compared with Control group, the expression of PRMT2 was significantly down-regulated in ox-LDL group (P < 0.05). A large number of red lipid droplets appeared in the cells in Vector group. Compared with Vector group, lipid droplets, the levels of TC, FC and CE and CE/TC, cholesterol efflux rate and expression of ABCA1 in RAW 264.7 macrophage was significantly decreased in LV-PRMT2 group (all P < 0.05). There was no significant difference about the expressions of ABCG1, CD36 and SR-A1 between LV-PRMT2 group and Vector group (all P > 0.05). CONCLUSIONS: Overexpression of PRMT2 inhibits the formation of foam cell induced by ox-LDL in RAW 264.7 macrophage, and the mechanism may be related to the increase of ABCA1 expression and ABCA1 mediated cholesterol efflux.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Células Espumosas/metabolismo , Lipoproteínas LDL/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Arginina/metabolismo , Aterosclerose/metabolismo , Transporte Biológico , Antígenos CD36/metabolismo , Regulação da Expressão Gênica , Lentivirus/genética , Metilação , Camundongos , Células RAW 264.7 , RNA Mensageiro/metabolismo , Receptores Depuradores/metabolismo , Transfecção
20.
Arterioscler Thromb Vasc Biol ; 40(3): 597-610, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31996021

RESUMO

OBJECTIVE: By binding to its high-affinity receptor FcεR1, IgE activates mast cells, macrophages, and other inflammatory and vascular cells. Recent studies support an essential role of IgE in cardiometabolic diseases. Plasma IgE level is an independent predictor of human coronary heart disease. Yet, a direct role of IgE and its mechanisms in cardiometabolic diseases remain incompletely understood. Approach and Results: Using atherosclerosis prone Apoe-/- mice and IgE-deficient Ige-/- mice, we demonstrated that IgE deficiency reduced atherosclerosis lesion burden, lesion lipid deposition, smooth muscle cell and endothelial cell contents, chemokine MCP (monocyte chemoattractant protein)-1 expression and macrophage accumulation. IgE deficiency also reduced bodyweight gain and increased glucose and insulin sensitivities with significantly reduced plasma cholesterol, triglyceride, insulin, and inflammatory cytokines and chemokines, including IL (interleukin)-6, IFN (interferon)-γ, and MCP-1. From atherosclerotic lesions and peritoneal macrophages from Apoe-/-Ige-/- mice that consumed an atherogenic diet, we detected reduced expression of M1 macrophage markers (CD68, MCP-1, TNF [tumor necrosis factor]-α, IL-6, and iNOS [inducible nitric oxide synthase]) but increased expression of M2 macrophage markers (Arg [arginase]-1 and IL-10) and macrophage-sterol-responsive-network molecules (complement C3, lipoprotein lipase, LDLR [low-density lipoprotein receptor]-related protein 1, and TFR [transferrin]) that suppress macrophage foam cell formation. These IgE activities can be reproduced in bone marrow-derived macrophages from wild-type mice, but muted in cells from FcεR1-deficient mice, or blocked by anti-IgE antibody or complement C3 deficiency. CONCLUSIONS: IgE deficiency protects mice from diet-induced atherosclerosis, obesity, glucose tolerance, and insulin resistance by regulating macrophage polarization, macrophage-sterol-responsive-network gene expression, and foam cell formation.


Assuntos
Aorta/metabolismo , Aterosclerose/metabolismo , Células Espumosas/metabolismo , Imunoglobulina E/metabolismo , Inflamação/metabolismo , Ativação de Macrófagos , Macrófagos Peritoneais/metabolismo , Obesidade/metabolismo , Animais , Aorta/imunologia , Aorta/patologia , Aterosclerose/imunologia , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Glicemia/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Células Espumosas/imunologia , Células Espumosas/patologia , Redes Reguladoras de Genes , Imunoglobulina E/deficiência , Imunoglobulina E/genética , Inflamação/imunologia , Inflamação/patologia , Inflamação/prevenção & controle , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Obesidade/imunologia , Obesidade/patologia , Obesidade/prevenção & controle , Fenótipo , Placa Aterosclerótica , Receptores de IgE/genética , Receptores de IgE/metabolismo , Transdução de Sinais , Esteróis/metabolismo
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