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1.
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
2.
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
3.
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
4.
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
5.
Gene ; 729: 144319, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31884108

RESUMO

In previous study, we have found that microRNA-23a is down regulated in atherosclerotic tissues. Here we demonstrate that miR-23a directly binds to 3'UTR of HSP90 mRNA to suppress the expression of HSP90. To investigate the potential roles of miR-23a in macrophage, THP-1 macrophages were transfected with miR-23a mimics or inhibitors. Our results showed inflammatory factors IL-6 and MCP-1 concentrations in cell culture medium of macrophage and foam cell transfected with miR-23a mimics were decreased. Furthermore, we find that apoptosis of macrophage and foam cells transfected with miR-23a mimics were inhibited. Over expression of miR-23a in foam cells could reduced lipid intake and accumulation in foam cells. Meanwhile, we found that in inflammatory macrophages and foam cells transfected with miR-23a mimcs, HSP90 and NF-κB proteins are significantly decreased. Our results have suggested a promising and potential therapeutic target for atherosclerosis.


Assuntos
Aterosclerose/genética , Aterosclerose/patologia , Células Espumosas/patologia , Proteínas de Choque Térmico HSP90/genética , Macrófagos/patologia , MicroRNAs/genética , Regiões 3' não Traduzidas , Apoptose/genética , Aterosclerose/metabolismo , Proliferação de Células/genética , Células Espumosas/metabolismo , Humanos , Inflamação/genética , Macrófagos/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Células THP-1
6.
DNA Cell Biol ; 38(12): 1499-1511, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31804889

RESUMO

Although long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been suggested to play important roles in the pathogenesis of diseases, atherosclerosis-related lncRNAs and circRNAs remain rarely reported. This study aimed to explore the underlying molecular mechanisms of atherosclerosis based on the competing endogenous RNA (ceRNA) regulatory hypothesis of lncRNAs and circRNAs. The expression profiles of circRNAs, lncRNAs, and mRNAs in human THP-1 macrophages treated with oxidized low-density lipoprotein (an in vitro atherosclerosis model), or not, were obtained from the Gene Expression Omnibus database under accession numbers GSE107522, GSE54666, and GSE54039, respectively. The present study identified 29 differentially expressed circRNAs in GSE107522, 544 differentially expressed genes (DEGs) in GSE54666, and 502 DEGs and 231 differentially expressed lncRNAs in GSE54039 datasets by using the Linear Models for Microarray Data method. Eight DEGs were found to be shared and expressed with the consistent trend in GSE54666 and GSE54039 datasets. Two of them (ASPH, aspartate beta-hydroxylase; and PDE3B, phosphodiesterase 3B) were suggested to be crucial based on functional enrichment, protein-protein interaction, and ceRNA network analyses. ASPH, through interaction with CACNA2D4 (calcium voltage-gated channel auxiliary subunit alpha2delta 4), may be associated with atherosclerosis by regulating the cellular response to calcium ion; and PDE3B may exert roles in negative regulation of angiogenesis through cross talk with ELMO1 (engulfment and cell motility 1). Furthermore, the expression of ASPH and PDE3B may be regulated by hsa_circ_0028198/hsa_circ_0092317/XIST-miR-543; PDE3B expression may be also modulated by hsa_circ_0092317/hsa_circ_0003546/H19/XIST-miR-326. In conclusion, our identified ceRNA interaction axes may possibly be important targets for treatment of atherosclerosis.


Assuntos
Células Espumosas/metabolismo , Lipoproteínas LDL/administração & dosagem , Macrófagos/metabolismo , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Células Cultivadas , Células Espumosas/citologia , Células Espumosas/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Oxirredução
7.
Int J Mol Sci ; 20(15)2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31382484

RESUMO

Arterial foam cells are central players of atherogenesis. Cholesterol acceptors, apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL), take up cholesterol and phospholipids effluxed from foam cells into the circulation. Due to the high abundance of cholesterol in foam cells, most previous studies focused on apoA-I/HDL-mediated free cholesterol (FC) transport. However, recent lipidomics of human atherosclerotic plaques also identified that oxidized sterols (oxysterols) and non-sterol lipid species accumulate as atherogenesis progresses. While it is known that these lipids regulate expression of pro-inflammatory genes linked to plaque instability, how cholesterol acceptors impact the foam cell lipidome, particularly oxysterols and non-sterol lipids, remains unexplored. Using lipidomics analyses, we found cholesterol acceptors remodel foam cell lipidomes. Lipid subclass analyses revealed various oxysterols, sphingomyelins, and ceramides, species uniquely enriched in human plaques were significantly reduced by cholesterol acceptors, especially by apoA-I. These results indicate that the function of lipid-poor apoA-I is not limited to the efflux of cholesterol and phospholipids but suggest that apoA-I serves as a major regulator of the foam cell lipidome and might play an important role in reducing multiple lipid species involved in the pathogenesis of atherosclerosis.


Assuntos
Colesterol/metabolismo , Células Espumosas/metabolismo , Placa Aterosclerótica/metabolismo , Animais , Apolipoproteína A-I/metabolismo , Aterosclerose/metabolismo , Células Cultivadas , Humanos , Lipoproteínas LDL/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Oxisteróis/metabolismo
8.
Mol Immunol ; 112: 387-393, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288148

RESUMO

Programmed cell death 4 (Pdcd4) was found to be related to apoptosis upon first discovery. It was later found to play the role of tumor suppressor gene in a variety of tumors by inhibiting transcription and translation. Recently, it has been proposed that it may play an important role in some inflammatory diseases and in the immune response. In our previous study, deficiency of Pdcd4 was found to attenuate the formation of atherosclerotic plaques. This might be because deficiency of Pdcd4 may increase IL-10 expression and lipoautophagy by macrophages and attenuate the formation of foam cells. However, the effect of Pdcd4 on the subsets of T cells in hyperlipidemic mice still remained unclear. In the present study, results showed that Pdcd4 deficiency decreased the percentage of CD8+ T cells and increased that of regulatory T cells (Tregs) under hyperlipidemic conditions both in vitro and in vivo, which may be due to the reduced expression of co-stimulatory molecules CD28 and CD137, and the enhancive expression of co-inhibitory molecules CTLA-4. These results indicated that endogenous Pdcd4 promotes immune response mediated by T cells through regulation of the co-stimulatory molecules expression, which may contribute to the development of advanced atherosclerotic plaques. The current work provides new data to understand the role of Pdcd4 in different T cell subsets under hyperlipidemic microenvironment.


Assuntos
Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/metabolismo , Hiperlipidemias/metabolismo , Proteínas de Ligação a RNA/metabolismo , Subpopulações de Linfócitos T/metabolismo , Animais , Apoptose/fisiologia , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Espumosas/metabolismo , Interleucina-10/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
9.
J Agric Food Chem ; 67(25): 7157-7166, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31146527

RESUMO

Lonicera caerulea berry polyphenols (LCBP) are known to reduce cholesterol accumulation. Currently, it is unknown whether LCBP can activate Sirtuin 1 (SIRT1) to regulate the formation of RAW264.7 macrophage foam cells. In this study, the effect of LCBP on lipid accumulation in macrophages was evaluated. Fluorescently labeled ox-LDL and 25-NBD cholesterol were used to detect the ox-LDL uptake and cholesterol outflow rate from macrophages. Gene silencing was performed using siRNA to detect changes in the expression of the ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding protein 2 (SREBP2), and SIRT1 proteins using Western blotting, and changes in the expression of miR-33 were detected by real-time polymerase chain reaction. The results showed that treatment with 80 µg/mL LCBP significantly inhibited the accumulation of lipids in RAW264.7 macrophages induced by ox-LDL and reduced intracellular cholesterol levels by activating SIRT1 to enhance the expression of ABCA1, a cholesterol efflux gene, but not independent effect. Of the three key LCBP components investigated, chlorogenic acid was found to activate SIRT1 and regulate the expression of the cholesterol-related factors ABCA1, SREBP2, and miR-33; cyanidin-3-glucoside and catechins were effective to a lesser extent. Our results suggest a novel hypolipidemic mechanism of LCBP.


Assuntos
Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Lonicera/química , Macrófagos/efeitos dos fármacos , Polifenóis/farmacologia , Sirtuína 1/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Células Espumosas/metabolismo , Frutas/química , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Sirtuína 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
10.
Biol Pharm Bull ; 42(6): 923-928, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155588

RESUMO

Macrophages endocytose modified low-density lipoproteins (LDL) vigorously via scavenger receptor A (SR-A) to become foam cells. In the present study, we found that Sac1, a member of the Sac family of phosphoinositide phosphatases, increases the protein level of SR-A and upregulates foam cell formation. Mouse macrophages (RAW264.7) were transfected with short hairpin RNAs (shRNAs) against Sac1. Sac1 knockdown decreased cell surface SR-A levels and impaired acetylated LDL-induced foam cell formation. Transfection of Sac1-knockdown cells with shRNA-resistant flag-Sac1 effectively rescued the expression of SR-A. Glycosylation of SR-A was largely attenuated by Sac1 knockdown, but neither mRNA expression nor protein degradation of SR-A were affected. These results suggest that Sac1 maintains SR-A protein levels by modulating SR-A glycosylation.


Assuntos
Células Espumosas/metabolismo , Proteínas de Membrana/metabolismo , Fosfatases de Fosfoinositídeos/metabolismo , Receptores Depuradores Classe A/metabolismo , Animais , Lipoproteínas LDL/metabolismo , Proteínas de Membrana/genética , Camundongos , Fosfatases de Fosfoinositídeos/genética , Células RAW 264.7 , RNA Mensageiro , RNA Interferente Pequeno , Receptores Depuradores Classe A/genética
11.
Biofactors ; 45(5): 763-773, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31237721

RESUMO

Foam cells are specialized types of cells which predominate the necrotic core of atherosclerotic plaque. Recently, autophagy-mediated cholesterol efflux from foam cells has been proposed as a beneficial therapy for atherosclerosis. The purpose of this study was to delineate the underlying molecular mechanism of oligomeric proanthocyanidins (OPC) and epigallocatechin gallate (EGCG) induced autophagy of foam cells and associated cholesterol efflux. The oxidized low-density lipoprotein induced foam cells demonstrated impaired autophagy flux through the downregulated expressions of LC3BII/LC3BI, autophagy related gene-5, Class III phosphoinositide 3 kinase (Class III PI3K), Beclin1, ABCA1, and ABCG1 with concomitant increase in the expressions of protein 62, Class I phosphoinositide 3 kinase, Akt, and mammalian target of rapamycin. However, these effects were significantly abolished by treatment with OPC and EGCG through activation of autophagy flux via Class III PI3K/Beclin1 and with upregulated expression of transporter proteins ABCA1 and ABCG1. Furthermore, the cholesterol efflux process in the foam cells was activated by lysosomal acid lipase and cathepsin D facilitated lipolysis of lipid droplets. Taken together, our data demonstrate that OPC and EGCG treatment stimulated the coordinated activation of autophagy and cholesterol efflux through Class III PI3K/Beclin1 pathway in foam cells, suggesting a promising therapeutic strategy against atherosclerosis.


Assuntos
Proteína Beclina-1/genética , Catequina/análogos & derivados , Colesterol/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/genética , Células Espumosas/efeitos dos fármacos , Proantocianidinas/farmacologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Catequina/farmacologia , Cromonas/farmacologia , Classe III de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Inibidores Enzimáticos/farmacologia , Células Espumosas/citologia , Células Espumosas/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Morfolinas/farmacologia , Fagossomos/efeitos dos fármacos , Fagossomos/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Células THP-1 , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
12.
Int J Mol Sci ; 20(9)2019 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-31060209

RESUMO

Legumain, a recently discovered cysteine protease, is increased in both carotid plaques and plasma of patients with carotid atherosclerosis. Legumain increases the migration of human monocytes and human umbilical vein endothelial cells (HUVECs). However, the causal relationship between legumain and atherosclerosis formation is not clear. We assessed the expression of legumain in aortic atheromatous plaques and after wire-injury-induced femoral artery neointimal thickening and investigated the effect of chronic legumain infusion on atherogenesis in Apoe-/- mice. We also investigated the associated cellular and molecular mechanisms in vitro, by assessing the effects of legumain on inflammatory responses in HUVECs and THP-1 monocyte-derived macrophages; macrophage foam cell formation; and migration, proliferation, and extracellular matrix protein expression in human aortic smooth muscle cells (HASMCs). Legumain was expressed at high levels in atheromatous plaques and wire injury-induced neointimal lesions in Apoe-/- mice. Legumain was also expressed abundantly in THP-1 monocytes, THP-1 monocyte-derived macrophages, HASMCs, and HUVECs. Legumain suppressed lipopolysaccharide-induced mRNA expression of vascular cell adhesion molecule-1 (VCAM1), but potentiated the expression of interleukin-6 (IL6) and E-selectin (SELE) in HUVECs. Legumain enhanced the inflammatory M1 phenotype and oxidized low-density lipoprotein-induced foam cell formation in macrophages. Legumain did not alter the proliferation or apoptosis of HASMCs, but it increased their migration. Moreover, legumain increased the expression of collagen-3, fibronectin, and elastin, but not collagen-1, in HASMCs. Chronic infusion of legumain into Apoe-/- mice potentiated the development of atherosclerotic lesions, accompanied by vascular remodeling, an increase in the number of macrophages and ASMCs, and increased collagen-3 expression in plaques. Our study provides the first evidence that legumain contributes to the induction of atherosclerotic vascular remodeling.


Assuntos
Aterosclerose/metabolismo , Aterosclerose/patologia , Cisteína Endopeptidases/metabolismo , Remodelação Vascular , Animais , Apoptose , Aterosclerose/etiologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisteína Endopeptidases/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Matriz Extracelular/metabolismo , Células Espumosas/metabolismo , Células Espumosas/patologia , Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Knockout , Neointima/metabolismo , Neointima/patologia
13.
Circ Res ; 124(10): 1505-1518, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31071007

RESUMO

Cardiovascular disease, with atherosclerosis as the major underlying factor, remains the leading cause of death worldwide. It is well established that cholesterol ester-enriched foam cells are the hallmark of atherosclerotic plaques. Multiple lines of evidence support that enhancing foam cell cholesterol efflux by HDL (high-density lipoprotein) particles, the first step of reverse cholesterol transport (RCT), is a promising antiatherogenic strategy. Yet, excitement towards the therapeutic potential of manipulating RCT for the treatment of cardiovascular disease has faded because of the lack of the association between cardiovascular disease risk and what was typically measured in intervention trials, namely HDL cholesterol, which has an inconsistent relationship to HDL function and RCT. In this review, we will summarize some of the potential reasons for this inconsistency, update the mechanisms of RCT, and highlight conditions in which impaired HDL function or RCT contributes to vascular disease. On balance, the evidence still argues for further research to better understand how HDL functionality contributes to RCT to develop prevention and treatment strategies to reduce the risk of cardiovascular disease.


Assuntos
Aterosclerose/terapia , Doenças Cardiovasculares/terapia , Colesterol/metabolismo , Células Espumosas/metabolismo , Lipoproteínas HDL/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/etiologia , Aterosclerose/metabolismo , Autofagia/fisiologia , Transporte Biológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/metabolismo , Humanos , Vasos Linfáticos/metabolismo , Músculo Liso Vascular/citologia , Placa Aterosclerótica/patologia
14.
Acta Biochim Biophys Sin (Shanghai) ; 51(5): 471-483, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30950489

RESUMO

Sortilin is closely associated with hyperlipidemia and the risk of atherosclerosis (AS). The role of sortilin and the underlying mechanism in peripheral macrophage are not fully understood. In this study, we investigated the effect of macrophage sortilin on ATP-binding cassette transporter A1 (ABCA1) expression, ABCA1-mediated cholesterol efflux, and aortic AS. Macrophage sortilin expression was upregulated by oxidized low-density lipoproteins (ox-LDLs) in both concentration- and time-dependent manners. Its expression reached the peak level when cells were incubated with 50 µg/ml ox-LDL for 24 h. Overexpression of sortilin in macrophage reduced cholesterol efflux, leading to an increase in intracellular total cholesterol, free cholesterol, and cholesterol ester. Sortilin was found to bind with ABCA1 protein and suppress macrophage ABCA1 expression, resulting in a decrease in cholesterol efflux from macrophages. The inhibitory effect of sortilin in cholesterol efflux was partially reversed by treatment with chloroquine, a lysosomal inhibitor. On the contrary, the ABCA1 protein level and ABCA1-mediated cholesterol efflux is increased by sortilin short hairpin RNA transfection. The fecal and biliary cholesterol 3H-sterol from cholesterol-laden mouse peritoneal macrophage was reduced by sortilin overexpression through lentivirus vector (LV)-sortilin in low-density lipoprotein receptor knockout mice, which was prevented by co-treatment with chloroquine. Treatment with LV-sortilin reduced plasma high-density lipoprotein and increased plasma ox-LDL levels. Accordingly, aortic lipid deposition and plaque area were exacerbated, and ABCA1 expression was reduced in mice in response to infection with LV-sortilin alone. These effects of LV-sortilin were partially reversed by chloroquine. Sortilin enhances lysosomal degradation of ABCA1 protein and suppresses ABCA1-mediated cholesterol efflux from macrophages, leading to foam cell formation and AS development.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Aterosclerose/metabolismo , Colesterol/metabolismo , Lisossomos/metabolismo , Macrófagos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Aterosclerose/genética , Células Cultivadas , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Interferência de RNA , Receptores de LDL/genética , Receptores de LDL/metabolismo , Células THP-1
15.
Biomed Pharmacother ; 115: 108880, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31035012

RESUMO

Advanced glycation end products (AGEs) are closely associated with diabetic macrovascular complications. The present study aimed to investigate the effects of Nε-Carboxymethyl-Lysine (the key active component of AGEs) in diabetic atherosclerosis on foam cell apoptosis and to explore the underlying mechanisms. Tissue sections were collected from 12 Type 2 diabetic patients and 4 control patients who underwent amputation surgery following a car accident. Peritoneal injection of streptozotocin in ApoE-/- mice was used to generate a diabetic model in vivo, and Raw 264.7 cells treated with CML and 740Y-P (a PI3K/AKT signaling agonist) were used to explore the effect of PI3K/AKT signaling in CML-induced foam cell apoptosis in vitro. The anterior tibial section of diabetic amputees contained a thinner fiber cap, higher lipid content, and more apoptotic cells than were found in control patients. in vitro studies using Raw 264.7 cell-derived foam cells and in vivo studies using diabetic ApoE-/- mice showed that CML levels dose-dependently reduced cell vitality, induced foam cell apoptosis and regulated apoptosis related protein. Furthermore, CML significantly decreased the phosphorylation of PI3K/AKT signaling, and restoration of PI3K/AKT signaling by 740Y-P decreased the CML-induced foam cell apoptosis. In conclusion, our results showed CML induced foam cell apoptosis in diabetic atherosclerosis through inhibiting the PI3K/AKT pathway.


Assuntos
Apoptose/efeitos dos fármacos , Aterosclerose/induzido quimicamente , Células Espumosas/efeitos dos fármacos , Lisina/análogos & derivados , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Aterosclerose/patologia , Diabetes Mellitus/patologia , Células Espumosas/metabolismo , Humanos , Lipoproteínas LDL/toxicidade , Lisina/farmacologia , Camundongos , Camundongos Knockout para ApoE , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Células RAW 264.7 , Artérias da Tíbia/patologia
16.
Immunity ; 50(4): 941-954, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995508

RESUMO

Arterial inflammation is a hallmark of atherosclerosis, and appropriate management of this inflammation represents a major unmet therapeutic need for cardiovascular disease patients. Here, we review the diverse contributions of immune cells to atherosclerosis, the mechanisms of immune cell activation in this context, and the cytokine circuits that underlie disease progression. We discuss the recent application of these insights in the form of immunotherapy to treat cardiovascular disease and highlight how studies on the cardiovascular co-morbidity that arises in autoimmunity might reveal additional roles for cytokines in atherosclerosis. Currently, data point to interleukin-1ß (IL-1ß), tumor necrosis factor (TNF), and IL-17 as cytokines that, at least in some settings, are effective targets to reduce cardiovascular disease progression.


Assuntos
Doenças Cardiovasculares/imunologia , Citocinas/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Cardiovasculares/tratamento farmacológico , Colesterol/metabolismo , Ensaios Clínicos como Assunto , Citocinas/antagonistas & inibidores , Citocinas/uso terapêutico , Progressão da Doença , Células Espumosas/imunologia , Células Espumosas/metabolismo , Microbioma Gastrointestinal , Humanos , Inflamassomos/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-1beta/antagonistas & inibidores , Camundongos Knockout , Modelos Imunológicos , Músculo Liso Vascular/imunologia , Fagócitos/imunologia , Fagócitos/metabolismo , Transdução de Sinais , Suínos , Pesquisa Médica Translacional
17.
Biochem Biophys Res Commun ; 512(1): 41-48, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30853183

RESUMO

Foam cell formation plays an important role in the initiation and progression of atherosclerosis. Aldehyde dehydrogenase 2 (ALDH2), a key enzyme for aldehyde metabolism, is associated with coronary artery disease and affects atherosclerotic plaque vulnerability. However, the role of ALDH2 in foam cell formation remains unclear. Using peritoneal macrophages from ALDH2-deficient and control mice, we found that ALDH2 deficiency suppressed foam cell formation induced by oxidized low-density lipoproteins (ox-LDL) but not acetylated low-density lipoproteins (ac-LDL) ex vivo. After incubation with ox-LDL, ALDH2-deficient macrophages expressed lower levels of CD36 but the expression of other lipid metabolism-related proteins including SRA, LOX-1, ABCA-1, ABCG-1 and ACAT-1 was not changed in ALDH2-/- macrophages. Using CD36 inhibitor, we confirmed that CD36 contributes to the effect of ALDH2 on foam cell formation. PPARγ was downregulated in ox-LDL treated ALDH2-/- macrophages. 4-HNE was increased by ALDH2 deficiency and high concentration of 4-HNE suppressed the expression of PPARγ. These data suggest that ALDH2 plays an important role in foam cell formation via 4-HNE/PPARγ/CD36 pathway.


Assuntos
Aldeído-Desidrogenase Mitocondrial/deficiência , Antígenos CD36/metabolismo , Células Espumosas/metabolismo , Lipoproteínas LDL/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Aldeídos/metabolismo , Aldeídos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Regulação para Baixo , Células Espumosas/efeitos dos fármacos , Células Espumosas/patologia , Técnicas In Vitro , Lipoproteínas LDL/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Cardiovasculares , PPAR gama/metabolismo , Transdução de Sinais
18.
Cell Physiol Biochem ; 52(4): 681-695, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30921507

RESUMO

BACKGROUND/AIMS: Oxidative modifications of low-density lipoprotein (ox-LDL) play a key role in initial steps of atheroprogression possibly via specific scavenger receptors on inflammatory and endothelial cells. Amongst others, CD68 might play a crucial role in this leading to fatty streak formation. METHODS: Different CD68-Fc fusion proteins were cloned, expressed and tested in vitro for their oxLDL binding properties as a decoy for endogenous oxLDL. Physiological functions were tested in foam cell assays with human monocytes in culture and by binding oxLDL from human blood. The best suited candidate FcIgG2-FL-CD68 was injected twice weekly in LDL receptor and ApoBec deficient mice (LDLR-/-/Apobec-/-), and the oxLDL content was measured in peripheral blood, in different cell types of the spleen and aortic wall by specific oxLDL antibodies using flow cytometry. RESULTS: Different variants of the CD68-Fc bound to copper-oxided LDL (oxLDL), LDL and to a lesser extent HDL with different efficacy in an ELISA based binding assay in vitro. Native oxLDL content in human blood derived from patients with extended atherosclerosis was reduced after passage through a specific protein G column conjugated with the different CD68-Fc fusion proteins. Foam cell formation from human peripheral blood monocyte-platelet co-culture was reduced by the most effective CD68-Fc fusion proteins. oxLDL was not increased in the blood but markedly increased in the vessel wall from LDLR-/-/Apobec-/- mice at an early stage of atherosclerosis. Platelet-like cells in the vessel well contributed most to the increase in tissue oxLDL. FcIgG2-FL-CD68, reduced oxLDL content of aortic vessel wall cells from LDLR-/-/Apobec-/- mice. However a tissue specific reduction on the oxLDL content in peripheral blood, the spleen or cells from the aortic vessel by FcIgG2-FL-CD68 could not be shown. CONCLUSION: Platelets contribute to increased tissue oxLDL in the aortic wall but not in peripheral blood. CD68 seems to play a role in the oxLDL metabolism in the vessel wall at early stages of atherosclerosis. FcIgG2-FL-CD68 could serve as a novel therapeutic option to modify the oxLDL content in the vessel wall.


Assuntos
Desaminase APOBEC-1/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Plaquetas/metabolismo , Lipoproteínas LDL/genética , Desaminase APOBEC-1/deficiência , Animais , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Plaquetas/citologia , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Modelos Animais de Doenças , Células Espumosas/citologia , Células Espumosas/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/análise , Lipoproteínas LDL/deficiência , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução , Ligação Proteica , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação
20.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1402-1409, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776415

RESUMO

The nuclear receptor liver X receptor (LXR) impacts on cholesterol metabolism as well as hepatic lipogenesis via transcriptional regulation. It is proposed that inhibition of the protein arginine methyltransferase 3 (PRMT3) uncouples these two transcriptional pathways in vivo by acting as a specific lipogenic coactivator of LXR. Here we validated the hypothesis that treatment with the allosteric PRMT3 inhibitor SGC707 will diminish the hepatic steatosis extent, while leaving global cholesterol metabolism, important in cholesterol-driven pathologies like atherosclerosis, untouched. For this purpose, 12-week old hyperlipidemic apolipoprotein E knockout mice were fed a Western-type diet for six weeks to induce both hepatic steatosis and atherosclerosis. The mice received 3 intraperitoneal injections with SGC707 or solvent control per week. Mice chronically treated with SGC707 developed less severe hepatic steatosis as exemplified by the 51% reduced (P < 0.05) liver triglyceride levels. In contrast, the extent of in vivo macrophage foam cell formation and aortic root atherosclerosis was not affected by SGC707 treatment. Interestingly, SGC707-treated mice gained 94% less body weight (P < 0.05), which was paralleled by changes in white adipose tissue morphology, i.e. reduction in adipocyte size and browning. In conclusion, we have shown that through PRMT3 inhibitor treatment specific functions of LXR involved in respectively the development of fatty liver disease and atherosclerosis can be uncoupled, resulting in an overall diminished hepatic steatosis extent without a negative impact on atherosclerosis susceptibility. As such, our studies highlight that PRMT3 inhibition may constitute a novel therapeutic approach to limit the development of fatty liver disease in humans.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/genética , Inibidores Enzimáticos/farmacologia , Fígado Gorduroso/prevenção & controle , Isoquinolinas/farmacologia , Proteína-Arginina N-Metiltransferases/genética , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/enzimologia , Tecido Adiposo Branco/patologia , Regulação Alostérica/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/deficiência , Aterosclerose/enzimologia , Aterosclerose/etiologia , Aterosclerose/patologia , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Células Espumosas/patologia , Regulação da Expressão Gênica , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout para ApoE , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Transdução de Sinais , Triglicerídeos/metabolismo
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