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2.
Medicine (Baltimore) ; 99(32): e21608, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769918

RESUMO

BACKGROUND: Venous leg ulcers (VLUs) are common throughout the world, which seriously affects the patient's work and life. Relevant researches suggested that sclerosing foam (SF) has potential benefits for VLUs. However, there is no consistent conclusion. The purpose of our study is to assess whether SF is effective and safe for VLUs. METHODS: Relevant clinical randomized controlled trials will be obtained from a search of 8 databases (with no language restrictions) from their inception to May 2020: PubMed, the Cochrane Library, EMBASE, Web of Science, China National Knowledge Infrastructure Database, Wanfang Database, China Science and Technology Journal Database, and Chinese Biological Medicine. Data will be analyzed using RevMan 5.3 after literature screening and data extraction according to predefined inclusion and exclusion criteria. Cochrane Collaboration Risk of bias Tool will be applied in evaluating the quality of enrolled articles. The primary outcome is Closure of venous leg ulcers, ulcer healing rate, adverse events related to SF. The secondary outcomes include ulcer healing time, ulcer recurrence rate, pain. Risk ratio will be used for categorical data; mean differences will be used for measurement data. Where possible and appropriate, meta-analysis will be performed for each outcome. RESULTS: To clarify whether Sclerosing foam can be safe and efficient on treating venous leg ulcers. CONCLUSION: Our review will provide useful information to judge whether Sclerosing Foam is an effective and safe intervention for patients with venous leg ulcers.


Assuntos
Bandagens/normas , Protocolos Clínicos , Células Espumosas , Soluções Esclerosantes/uso terapêutico , Úlcera Varicosa/terapia , Humanos , Perna (Membro)/anormalidades , Perna (Membro)/irrigação sanguínea , Perna (Membro)/fisiopatologia , Metanálise como Assunto , Soluções Esclerosantes/normas , Revisões Sistemáticas como Assunto
3.
APMIS ; 128(8): 506-510, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32564430

RESUMO

This case report discusses a patient with nephrotic syndrome, pulmonary hypertension, and repeated episodes of infections. He had a history of intravenous drug abuse. Kidney biopsy revealed the rare finding of numerous foam cells, mainly in glomeruli. The solvent used for the drugs is thought to be responsible for the foam cells. In line with previous reports, we suspect that the pulmonary hypertension is consistent with foam cells in pulmonary capillaries or fat embolism syndrome due to the intravenous administered drugs. Our case demonstrates that the use of intravenous drugs can lead to widely varying symptoms. Globally, the prevalence of substance abuse is increasing. Knowledge about their damaging effects is crucial in both clinical practice and anatomic pathology.


Assuntos
Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Infecções/etiologia , Infecções/patologia , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/patologia , Abuso de Substâncias por Via Intravenosa/complicações , Adulto , Biópsia , Células Espumosas/patologia , Humanos , Hipertensão Pulmonar/complicações , Infecções/complicações , Rim/patologia , Masculino , Síndrome Nefrótica/complicações
4.
Life Sci ; 253: 117682, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32387418

RESUMO

Atherosclerosis is a disease in which lipid-laden plaques are developed inside the vessel walls of arteries. The immune system is activated, resulting in inflammation and oxidative stress. Endothelial cells (ECs) are activated, arterial smooth muscle cells (SMCs) proliferate, macrophages are activated, and foam cells are developed, leading to dysfunctional ECs. Epigenetic regulatory mechanisms, including DNA methylation, histone modifications, and microRNAs are involved in the modulation of genes that play distinct roles in several aspects of cell biology and physiology, hence linking environmental stimuli to gene regulation. Recent research has investigated the involvement of DNA methylation in the etiopathogenesis of atherosclerosis, and several studies have documented the role of this mechanism in various aspects of the disease. Regulation of DNA methylation plays a critical role in the integrity of ECs, SMC proliferation and formation of atherosclerotic lesions. In this review, we seek to clarify the role of DNA methylation in the development of atherosclerosis through different mechanisms.


Assuntos
Aterosclerose/patologia , Metilação de DNA , Epigênese Genética , Animais , Aterosclerose/genética , Células Endoteliais/patologia , Células Espumosas/patologia , Humanos , Inflamação/patologia , Miócitos de Músculo Liso/patologia , Estresse Oxidativo/genética , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia
6.
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
7.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(1): 17-23, 2020 Jan 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-32132293

RESUMO

OBJECTIVES: To explore the expression of autophagy related genes 5 (ATG5) and cyclin E in coronary heart disease (CHD) and its clinical significance. METHODS: From April 2018 to August 2018, 80 patients diagnosed with CHD in the Second Xiangya Hospital, Central South University were selected as an observation group, and another 80 healthy subjects were selected as a control group. The expression of ATG5 and cyclin E mRNA in nucleate cells and the plasma protein in the 2 groups were detected and analyzed. The model of macrophage-derived foam cells induced by oxidized low density lipoprotein (ox-LDL) was used to simulate atherosclerosis. The proliferation of macrophage- derived foam cells and the protein levels of ATG5 and cyclin E induced by ox-LDL at different concentrations were examined. RESULTS: Compared with the control group, the levels of ATG5 mRNA and protein in the blood in the observation group were decreased, and the cyclin E mRNA and protein levels were increased, there were statistically difference (both P<0.05). Receiver operating characteristic (ROC) curve showed that the area under curve (AUC) of ATG5 mRNA, cyclin E mRNA, ATG5 protein and cyclin E protein were 0.739, 0.780, 0.671 and 0.807, respectively. Pearson analysis showed that the ATG5 mRNA was negatively correlated with the cyclin E mRNA (r=-0.734, P<0.05),while the plasma ATG5 protein was negatively correlated with the plasma cyclin E protein (r=-0.746, P<0.05). Macrophage-derived foam cell model induced by ox-LDL showed that the proliferation of foam cells and the expression levels of cyclin E protein were increased in a concentration and time-dependent manner, and the expression levels of ATG5 protein were decreased in a concentration-dependent manner. CONCLUSIONS: The levels of ATG5 mRNA and protein are lowly expressed while the levels of cyclin E mRNA and protein are highly expressed in the patients with CHD.The ATG5 protein levels are lowly expressed in ox-LDL-treated macrophage-derived foam cells while the cyclin E protein levels are highly expressed in ox-LDL-treated macrophage-derived foam cells. Based on these observations, we conclude that ATG5 inhibits the degradation of the cyclin E and promotes the proliferation of macrophages, involving in the occurrence and development of CHD.


Assuntos
Autofagia , Doença das Coronárias , Proteína 5 Relacionada à Autofagia , Ciclina E , Células Espumosas , Humanos , Lipoproteínas LDL
8.
Arterioscler Thromb Vasc Biol ; 40(5): 1155-1167, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32212851

RESUMO

OBJECTIVES: During the advancement of atherosclerosis, plaque cellularity is governed by the influx of monocyte-derived macrophages and their turnover via apoptotic and nonapoptotic forms of cell death. Previous reports have demonstrated that programmed necrosis, or necroptosis, of plaque macrophages contribute to necrotic core formation. Knockdown or inhibition of the necrosome components RIPK1 (receptor-interacting protein kinase 1) and RIPK3 (receptor-interacting protein kinase 3) slow atherogenesis, and activation of the terminal step of necroptosis, MLKL (mixed lineage kinase domain-like protein), has been demonstrated in advanced human atherosclerotic plaques. However, whether MLKL directly contributes to lesion development and necrotic core formation has not been investigated. Approaches and Results: MLKL expression was knocked down in atherogenic Apoe-knockout mice via the administration of antisense oligonucleotides. During atherogenesis, Mlkl knockdown decreased both programmed cell death and the necrotic core in the plaque. However, total lesion area remained unchanged. Furthermore, treatment with the MLKL antisense oligonucleotide unexpectedly reduced circulating cholesterol levels compared with control antisense oligonucleotide but increased the accumulation of lipids within the plaque and in vitro in macrophage foam cells. MLKL colocalized with the late endosome and multivesicular bodies in peritoneal macrophages incubated with atherogenic lipoproteins. Transfection with MLKL antisense oligonucleotide increased lipid localization with the multivesicular bodies, suggesting that upon Mlkl knockdown, lipid trafficking becomes defective leading to enhanced lipid accumulation in macrophages. CONCLUSIONS: These studies confirm the requirement for MLKL as the executioner of necroptosis, and as such a significant contributor to the necrotic core during atherogenesis. We also identified a previously unknown role for MLKL in regulating endosomal trafficking to facilitate lipid handling in macrophages during atherogenesis.


Assuntos
Doenças da Aorta/enzimologia , Aterosclerose/enzimologia , Colesterol/metabolismo , Células Espumosas/enzimologia , Macrófagos Peritoneais/enzimologia , Placa Aterosclerótica , Proteínas Quinases/deficiência , Animais , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Endossomos/metabolismo , Feminino , Células Espumosas/patologia , Macrófagos Peritoneais/patologia , Masculino , Camundongos Knockout para ApoE , Necroptose , Necrose , Oligonucleotídeos Antissenso/administração & dosagem , Proteínas Quinases/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais
10.
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
11.
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
12.
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
13.
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
14.
Scand J Immunol ; 91(4): e12866, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31960452

RESUMO

Understanding mechanisms of cavitation in tuberculosis (TB) is the missing link that could advance the field towards better control of the infection. Descriptions of human TB suggest that postprimary TB begins as lipid pneumonia of foamy macrophages that undergoes caseating necrosis and fragmentation to produce cavities. This study aimed to investigate the various mycobacterial antigens accumulating in foamy macrophages and their relation to tissue destruction and necrosis. Pulmonary tissues from mice with slowly progressive TB were studied for histopathology, acid-fast bacilli (AFB) and presence of mycobacterial antigens. Digital quantification using Aperio ImageScope was done. Until week 12 postinfection, mice were healthy, and lesions were small with scarce AFB and mycobacterial antigens. Colony-forming units (CFUs) increased exponentially. At week 16-33, mice were sick, macrophages attained foamy appearance with an increase in antigens (P < .05), 1.5 log increase in CFUs and an approximately onefold increase in AFB. At week 37-41, mice started dying with a shift in morphology towards necrosis. A >20-fold increase in mycobacterial antigens was observed with only less than one log increase in CFUs and sevenfold increase in AFB. Secreted antigens were significantly (P < .05) higher compared to cell-wall antigens throughout infection. Focal areas of necrosis were associated with an approximately 40-fold increase in antigen MPT46, functionally active thioredoxin, and a significant increase in all secreted antigens. In conclusion, mycobacterial antigens accumulate in the foamy macrophages in TB lesions during slowly progressive murine pulmonary TB. Secreted antigens and MPT46 correlated with necrosis, thereby implying that they might trigger the formation of cavities.


Assuntos
Antígenos de Bactérias/imunologia , Células Espumosas/imunologia , Células Espumosas/microbiologia , Tuberculose Pulmonar/patologia , Animais , Células Espumosas/patologia , Camundongos , Mycobacterium tuberculosis , Necrose , Tuberculose Pulmonar/imunologia
15.
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
16.
J Cardiovasc Pharmacol ; 75(1): 45-53, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31895879

RESUMO

Atherosclerosis is a chronic inflammation condition resulting from the interaction between lipoproteins, monocyte-derived macrophages, T lymphocytes, and other cellular elements in the arterial wall. Macrophage-derived foam cells play a key role in both early and advanced stage of atherosclerosis. Previous studies have shown that berberine could inhibit foam cell formation and prevent experimental atherosclerosis. However, its underlying molecular mechanisms have not been fully clarified. In this study, we explored the cholesterol-lowering effects of berberine in macrophage-derived foam cells and investigated its possible mechanisms in prevention and treatment of atherosclerosis. Here, we demonstrated that berberine could inhibit atherosclerosis in apolipoprotein E-deficient mice and induce cholesterol reduction as well as decrease the content of macrophages. Berberine can regulate oxLDL uptake and cholesterol efflux, thus suppresses foam cell formation. Mechanisms study showed that berberine can suppress scavenger receptor expression via inhibiting the activity of AP-1 and upregulate ATP-binding cassette transporter via activating Nrf2/HO-1 signaling in human macrophage. In summary, berberine significantly inhibits atherosclerotic disease development by regulating lipid homeostasis and suppressing macrophage foam cell formation.


Assuntos
Aterosclerose/prevenção & controle , Berberina/farmacologia , Colesterol/metabolismo , Antagonistas Colinérgicos/farmacologia , Células Espumosas/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator de Transcrição AP-1/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Antígenos CD36/metabolismo , Modelos Animais de Doenças , Células Espumosas/enzimologia , Células Espumosas/patologia , Heme Oxigenase-1/genética , Humanos , Lipoproteínas LDL/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Fator 2 Relacionado a NF-E2/genética , Receptores Depuradores Classe A/metabolismo , Células THP-1
17.
Mol Cell Biochem ; 463(1-2): 211-223, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31686316

RESUMO

Atherosclerosis is associated with deregulated cholesterol metabolism and formation of macrophage foam cells. CCAAT/enhancer-binding protein beta (C/EBPß) is a transcription factor, and its inhibition has recently been shown to prevent atherosclerosis development and foam cell formation. However, whether C/EBPß regulates inflammation, endoplasmic reticulum (ER) stress, and apoptosis, in macrophage foam cells and its underlying molecular mechanism remains unknown. Here, we investigated the effect of C/EBPß knockdown on proteins and genes implicated in inflammation, ER stress, apoptosis, and autophagy in macrophage foam cells. RAW264.7 macrophage cells were transfected with control and C/EBPß-siRNA and then treated with nLDL and oxLDL. Key proteins and genes involved in inflammation, ER stress, apoptosis, and autophagy were analyzed by western blot and qPCR. We found that short interfering RNA (siRNA)-mediated knockdown of C/EBPß attenuated atherogenic lipid-mediated induction of proteins and genes implicated in inflammation (P-NFkB-p65, NFkB-p65, and TNFα), ER stress (ATF4 and ATF6), and apoptosis (CHOP, caspase 1, 3, and 12). Interestingly, C/EBPß knockdown upregulated the expression of autophagy proteins (LC3A/B-II, ATG5) and genes (LC3B, ATG5) but decreased the mammalian target of rapamycin (mTOR) protein phosphorylation and mTORC1 gene expression in oxLDL-loaded RAW264.7 macrophage cells. More importantly, treatment with rapamycin (inhibitor of mTOR) increased expression of proteins implicated in autophagy and cholesterol efflux in oxLDL-loaded RAW 264.7 macrophage cells. The present results suggest that C/EBPß inactivation regulates macrophage foam cell formation in atherogenesis by reducing inflammation, ER stress, and apoptosis and by promoting autophagy and inactivating mTOR.


Assuntos
Apoptose , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Estresse do Retículo Endoplasmático , Células Espumosas/metabolismo , Regulação da Expressão Gênica , Lipoproteínas LDL/metabolismo , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Células Espumosas/patologia , Técnicas de Silenciamento de Genes , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Lipoproteínas LDL/genética , Camundongos , Células RAW 264.7
18.
Artigo em Inglês | MEDLINE | ID: mdl-31672574

RESUMO

A high consumption of polyunsaturated fatty acids (PUFAs), particularly n-3 PUFAs, is atheroprotective. PUFAs incorporation into membrane phospholipids alters the functionality of membrane proteins. We studied the consequences of the in vitro supplementation of several PUFAs on the FA profiles and on ABCA1-dependent cholesterol efflux capacities from cholesterol-loaded macrophages. Arachidonic acid (AA, C20:4 n-6) and, to a lesser extent, eicosapentaenoic acid (EPA, C20:5 n-3), dose-dependently impaired cholesterol efflux from cholesterol-loaded J774 mouse macrophages without alterations in ABCA1 expression, whereas docosahexaenoic acid (DHA, C22:6 n-3) had no impact. AA cells exhibited higher proportions of arachidonic acid and adrenic acid (C22:4 n-6), its elongation product. EPA cells exhibited slightly higher proportions of EPA associated with much higher proportions of docosapentaenoic acid (C22:5 n-3), its elongation product and with lower proportions of AA. Conversely, both EPA and DHA and, to a lesser extent, AA decreased cholesterol efflux from cholesterol-loaded primary human macrophages (HMDM). The differences observed in FA profiles after PUFA supplementations were different from those observed for the J774 cells. In conclusion, we are the first to report that AA and EPA, but not DHA, have deleterious effects on the cardioprotective ABCA1 cholesterol efflux pathway from J774 foam cells. Moreover, the membrane incorporation of PUFAs does not have the same impact on cholesterol efflux from murine (J774) or human (HMDM) cholesterol-loaded macrophages. This finding emphasizes the key role of the cellular model in cholesterol efflux studies and may partly explain the heterogeneous literature data on the impact of PUFAs on cholesterol efflux.


Assuntos
Ácido Araquidônico/administração & dosagem , Membrana Celular/efeitos dos fármacos , Colesterol/metabolismo , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Células Espumosas/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Colesterol/administração & dosagem , Colesterol/efeitos adversos , Suplementos Nutricionais , Células Espumosas/citologia , Células Espumosas/metabolismo , Voluntários Saudáveis , Humanos , Camundongos , Fosfolipídeos/metabolismo , Cultura Primária de Células
19.
Artigo em Inglês | MEDLINE | ID: mdl-31666189

RESUMO

Iron accumulation has been frequently found in atherosclerotic lesions, especially in macrophages/foam cells, but the exact mechanisms by which hepcidin induces iron retention in plaque macrophages and its roles in atherogenesis remain unknown. Double immunofluorescence staining showed colocalization of hepcidin-positive macrophages with ox-LDL, TLR4, p-p65 and ferritin light chain (ferritin-L) both in human and murine atherosclerotic lesions. RAW264.7 macrophages incubated with ox-LDL showed elevated expression of TLR4, p-p65, hepcidin, ferritin-L/H, CYP27A1, CD36, PPARγ, liver X receptor α (LXRα), and ATP binding cassette transporter A1/G1 (ABCA1/G1), as well as increased intracellular labile iron pool level and lipid accumulation. Ox-LDL-induced iron retention and lipid accumulation were aggravated by lipopolysaccharide but blocked by TAK-242, an antagonist of TLR4. Moreover, macrophage TLR4/NF-κB pathway activation and foaming triggered by ox-LDL was enhanced by ferric ammonium citrate or exogenous hepcidin but attenuated by hepcidin silencing or the use of iron chelator. Meanwhile, the addition of hepcidin stimulated CD36-mediated Dil-labeled-ox-LDL uptake and inhibited the LXRα-ABCA1/G1 pathway-dependent cholesterol efflux in macrophages, which was significantly reversed by 27-hydroxycholesterol but further exacerbated by cyclosporin A, a selective inhibitor of CYP27A1. Our study provided the evidence that iron trapped in atherosclerosis plaque macrophages contributes to cholesterol disequilibrium-initiated foam cell formation, which is provoked by the unique but largely unknown autocrine formation of hepcidin in plaque macrophages via activating the TLR4/NF-κB pathway when exposed to ox-LDL. Such findings, considering the intricate vicious cycle between macrophage hepcidin autocrine-triggered iron retention and cholesterol disequilibrium, may shed new light on the "iron hypothesis" of atherosclerosis.


Assuntos
Aterosclerose/patologia , Células Espumosas/metabolismo , Hepcidinas/metabolismo , Ferro/metabolismo , Placa Aterosclerótica/patologia , Idoso , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/cirurgia , Comunicação Autócrina , Artérias Carótidas/patologia , Artérias Carótidas/cirurgia , Colestanotriol 26-Mono-Oxigenase/metabolismo , LDL-Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Endarterectomia das Carótidas , Feminino , Humanos , Hidroxicolesteróis/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Camundongos , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , NF-kappa B , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/cirurgia , Células RAW 264.7 , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
20.
Arterioscler Thromb Vasc Biol ; 40(1): 86-102, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31597445

RESUMO

OBJECTIVE: Aggregation and modification of LDLs (low-density lipoproteins) promote their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of agLDL (aggregated LDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse. Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites, such as cholesterol, promotes foam cell formation, a process that drives atherogenesis. Furthermore, there is accumulating evidence for the involvement of TLR4 (Toll-like receptor 4) and its adaptor protein MyD88 (myeloid differentiation primary response 88) in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the lysosomal synapse and foam cell formation. Approach and Results: Using bone marrow-derived macrophages from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment, and foam cell formation. Using siRNA (small interfering RNA), pharmacological inhibition and knockout bone marrow-derived macrophages, we implicate SYK (spleen tyrosine kinase), PI3K (phosphoinositide 3-kinase), and Akt in agLDL catabolism using the lysosomal synapse. Using bone marrow transplantation of LDL receptor knockout mice with TLR4 knockout bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophages in vivo form an extracellular compartment and exocytose lysosome contents similar to that observed in vitro for degradation of agLDL. CONCLUSIONS: We present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the lysosomal synapse, catabolism of agLDL, and lipid accumulation in vitro and in vivo.


Assuntos
Aorta Torácica/metabolismo , Aterosclerose/metabolismo , Líquido Extracelular/metabolismo , Células Espumosas/metabolismo , Lipoproteínas LDL/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Aorta Torácica/patologia , Aterosclerose/patologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Células Espumosas/patologia , Immunoblotting , Camundongos , Camundongos Knockout , Transdução de Sinais
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