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1.
J Trace Elem Med Biol ; 67: 126786, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34022567

RESUMO

AIMS: Dysmetabolic iron overload syndrome (DIOS) is common but the clinical relevance of iron overload is not understood. Macrophages are central cells in iron homeostasis and inflammation. We hypothesized that iron overload in DIOS could affect the phenotype of monocytes and impair macrophage gene expression. METHODS: This study compared 20 subjects with DIOS to 20 subjects with metabolic syndrome (MetS) without iron overload, and 20 healthy controls. Monocytes were phenotyped by Fluorescence-Activated Cell Sorting (FACS) and differentiated into anti-inflammatory M2 macrophages in the presence of IL-4. The expression of 38 genes related to inflammation, iron metabolism and M2 phenotype was assessed by real-time PCR. RESULTS: FACS showed no difference between monocytes across the three groups. The macrophagic response to IL-4-driven differentiation was altered in four of the five genes of M2 phenotype (MRC1, F13A1, ABCA1, TGM2 but not FABP4), in DIOS vs Mets and controls demonstrating an impaired M2 polarization. The expression profile of inflammatory genes was not different in DIOS vs MetS. Several genes of iron metabolism presented a higher expression in DIOS vs MetS: SCL11A2 (a free iron transporter, +76 %, p = 0.04), SOD1 (an antioxidant enzyme, +27 %, p = 0.02), and TFRC (the receptor 1 of transferrin, +59 %, p = 0.003). CONCLUSIONS: In DIOS, macrophage polarization toward the M2 alternative phenotype is impaired but not associated with a pro-inflammatory profile. The up regulation of transferrin receptor 1 (TFRC) in DIOS macrophages suggests an adaptive role that may limit iron toxicity in DIOS.


Assuntos
Sobrecarga de Ferro , Síndrome Metabólica , Estudos de Casos e Controles , Humanos , Inflamação , Interleucina-4 , Ferro , Macrófagos
2.
Circ Res ; 121(1): 19-30, 2017 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-28438779

RESUMO

RATIONALE: Vascular calcification is a process similar to bone formation leading to an inappropriate deposition of calcium phosphate minerals in advanced atherosclerotic plaques. Monocyte-derived macrophages, located in atherosclerotic lesions and presenting heterogeneous phenotypes, from classical proinflammatory M1 to alternative anti-inflammatory M2 macrophages, could potentially display osteoclast-like functions. OBJECTIVE: To characterize the phenotype of macrophages located in areas surrounding the calcium deposits in human atherosclerotic plaques. METHODS AND RESULTS: Macrophages near calcium deposits display an alternative phenotype being both CD68 and mannose receptor-positive, expressing carbonic anhydrase type II, but relatively low levels of cathepsin K. In vitro interleukin-4-polarization of human primary monocytes into macrophages results in lower expression and activity of cathepsin K compared with resting unpolarized macrophages. Moreover, interleukin-4 polarization lowers expression levels of the osteoclast transcriptional activator nuclear factor of activated T cells type c-1, associated with increased gene promoter levels of the transcriptional repression mark H3K27me3 (histone 3 lysine 27 trimethylation). Despite higher expression of the receptor activator of nuclear factor κB receptor, receptor activator of nuclear factor κB ligand/macrophage colony-stimulating factor induction of nuclear factor of activated T cells type c-1 and cathepsin K expression is defective in these macrophages because of reduced Erk/c-fos-mediated downstream signaling resulting in impaired bone resorption capacity. CONCLUSIONS: These results indicate that macrophages surrounding calcium deposits in human atherosclerotic plaques are phenotypically defective being unable to resorb calcification.


Assuntos
Reabsorção Óssea/metabolismo , Macrófagos/metabolismo , Osteoclastos/metabolismo , Placa Aterosclerótica/metabolismo , Ligante RANK/metabolismo , Calcificação Vascular/metabolismo , Reabsorção Óssea/patologia , Células Cultivadas , Humanos , Microdissecção e Captura a Laser/métodos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Macrófagos/patologia , Osteoclastos/patologia , Placa Aterosclerótica/patologia , Calcificação Vascular/patologia
3.
Free Radic Biol Med ; 103: 146-154, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27988338

RESUMO

Whereas the anti-inflammatory properties and mechanisms of action of long chain ω3 PUFAs have been abundantly investigated, research gaps remain regarding the respective contribution and mechanisms of action of their oxygenated metabolites collectively known as oxylipins. We conducted a dose-dependent and comparative study in human primary macrophages aiming to compare the anti-inflammatory activity of two types of DHA-derived oxylipins including the well-described protectins (NPD1 and PDX), formed through lipoxygenase pathway and the neuroprostanes (14-A4t- and 4-F4t-NeuroP) formed through free-radical mediated oxygenation and expected to be new anti-inflammatory mediators. Considering the potential ability of these DHA-derived oxylipins to bind PPARs and knowing the central role of these transcription factors in the regulation of macrophage inflammatory response, we performed transactivation assays to compare the ability of protectins and neuroprostanes to activate PPARs. All molecules significantly reduced mRNA levels of cytokines such as IL-6 and TNF-α, however not at the same doses. NPD1 showed the most effect at 0.1µM (-14.9%, p<0.05 for IL-6 and -26.7%, p<0.05 for TNF-α) while the three other molecules had greater effects at 10µM, with the strongest result due to the cyclopentenone neuroprostane, 14-A4t-NeuroP (-49.8%, p<0.001 and -40.8%, p<0.001, respectively). Part of the anti-inflammatory properties of the DHA-derived oxylipins investigated could be linked to their activation of PPARs. Indeed, all tested oxylipins significantly activated PPARγ, with 14-A4t-NeuroP leading to the strongest activation, and NPD1 and PDX also activated PPARα. In conclusion, our results show that neuroprostanes and more especially cyclopentenone neuroprostanes have potent anti-inflammatory activities similar or even more pronounced than protectins supporting that neuroprostanes should be considered as important contributors to the anti-inflammatory effects of DHA.


Assuntos
Anti-Inflamatórios/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Macrófagos/imunologia , Neuroprostanos/farmacologia , Oxilipinas/farmacologia , Animais , Células COS , Células Cultivadas , Chlorocebus aethiops , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Expressão Gênica/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo
4.
Mol Metab ; 5(12): 1200-1207, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27900262

RESUMO

OBJECTIVE: The goal of the study was to investigate the role of histone deacetylases (HDACs) in adipocyte function associated with obesity and hypoxia. METHODS: Total proteins and RNA were prepared from human visceral adipose tissues (VAT) of human obese and normal weight subjects and from white adipose tissue (WAT) of C57Bl6-Rj mice fed a normal or high fat diet (HFD) for 16 weeks. HDAC activity was measured by colorimetric assay whereas the gene and protein expression were monitored by real-time PCR and by western blotting, respectively. RNA interference (RNAi) was used to silence the expression of genes in 3T3-L1 adipocytes. RESULTS: Total HDAC activity was decreased in VAT and WAT from obese individuals and from mice fed a HFD, respectively. The HDAC activity reduction was associated with decreased HDAC5/Hdac5 and HDAC6/Hdac6 expression in human and mice adipocyte fraction. Similarly, hypoxia hampered total Hdac activity and reduced the expression of Hdac5 and Hdac6 in 3T3-L1 adipocytes. The decrease of both Hdac5 and Hdac6 by hypoxia was associated with altered expression of adipokines and of the inducible cAMP early repressor (Icer), a key repressor that is defective in human and mice obesity. Silencing of Icer in adipocytes reproduced the changes in adipokine levels under hypoxia and obesity, suggesting a causative effect. Finally, modeling the defect of the two Hdacs in adipocytes by RNAi or selective inhibitors mimicked the effects of hypoxia on the expression of Icer, leading to impairment of insulin-induced glucose uptake. CONCLUSION: Hdac5 and Hdac6 expression are required for the adequate expression of Icer and adipocyte function. Altered adipose expression of the two Hdacs in obesity by hypoxia may contribute to the development of metabolic abnormalities.


Assuntos
Adipócitos/enzimologia , Desacetilase 6 de Histona/biossíntese , Histona Desacetilases/biossíntese , Obesidade/enzimologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/enzimologia , Adiposidade/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Hipóxia Celular/fisiologia , Modulador de Elemento de Resposta do AMP Cíclico/biossíntese , Modulador de Elemento de Resposta do AMP Cíclico/genética , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Dieta Hiperlipídica , Feminino , Desacetilase 6 de Histona/genética , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Gordura Intra-Abdominal/citologia , Gordura Intra-Abdominal/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia
5.
FEBS Lett ; 590(1): 43-52, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26763127

RESUMO

Macrophages display heterogeneous phenotypes, including the classical M1 proinflammatory and the alternative M2 anti-inflammatory polarization states. The transducin-like enhancer of split-1 (TLE1) is a transcriptional corepressor whose functions in macrophages have not been studied yet. We report that TLE1 is highly expressed in human alternative macrophages in vitro and in atherosclerotic plaques as well as in adipose tissue M1/M2 mixed macrophages. TLE1 silencing in alternative macrophages decreases the expression of the M2 markers IL-1Ra and IL-10, while it exacerbates TNFα and CCL3 induction by lipopolysaccharide. Hence, TLE1 is expressed in human macrophages where it has potential anti-inflammatory and alternative phenotype promoting properties.


Assuntos
Proteínas Correpressoras/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Proteínas Repressoras/metabolismo , Animais , Biomarcadores/metabolismo , Índice de Massa Corporal , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células Cultivadas , Proteínas Correpressoras/antagonistas & inibidores , Proteínas Correpressoras/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína Antagonista do Receptor de Interleucina 1/antagonistas & inibidores , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-10/antagonistas & inibidores , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucina-4/farmacologia , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos da Linhagem 129 , Obesidade/sangue , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/patologia , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Interferência de RNA , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética
6.
PPAR Res ; 2016: 5716415, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28077943

RESUMO

Peroxisome Proliferator-Activated Receptors (PPAR) are transcription factors suggested to be involved in inflammatory lesions of autoimmune encephalomyelitis and multiple sclerosis (MS). Our objective was to assess whether Natalizumab (NTZ) therapy is associated with alterations of PPAR expression in MS patients. We analyzed gene expression of PPAR in peripheral blood mononuclear cells (PBMC) as well as blood inflammatory markers in women with MS previously medicated with first-line immunomodulators (baseline) and after NTZ therapy. No differences in PPARα, PPARß/δ, PPARγ, and CD36 mRNA expression were found in PBMC between patients under baseline and healthy controls. At three months, NTZ increased PPARß/δ mRNA (p = 0.009) in comparison to baseline, while mRNA expression of PPARγ and CD36 (a well-known PPAR target gene) was lower in comparison to healthy controls (p = 0.026 and p = 0.028, resp.). Although these trends of alterations remain after six months of therapy, the results were not statistically significant. Osteopontin levels were elevated in patients (p = 0.002) and did not change during the follow-up period of NTZ treatment. These results suggest that PPAR-mediated processes may contribute to the mechanisms of action of NTZ therapy.

7.
Diab Vasc Dis Res ; 12(4): 279-89, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25966737

RESUMO

This study aimed to investigate atherosclerotic mediators' expression levels in M1 and M2 macrophages and to focus on the influence of diabetes on M1/M2 profiles. Macrophages from 36 atherosclerotic patients (19 diabetics and 17 non-diabetics) were cultured with interleukin-1ß (IL-1ß) or IL-4 to induce M1 or M2 phenotype, respectively. The atherosclerotic mediators' expression was evaluated by quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results showed that M1 and M2 macrophages differentially expressed mediators involved in proteolysis and angiogenesis processes. The proteolytic balance (matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1), MMP-9/plasminogen activator inhibitor-1 (PAI-1) and MMP-9/tissue factor pathway inhibitor-2 (TFPI-2) ratios) was higher in M1 versus M2, whereas M2 macrophages presented higher angiogenesis properties (increased vascular endothelial growth factor/TFPI-2 and tissue factor/TFPI-2 ratios). Moreover, M1 macrophages from diabetics displayed more important proangiogenic and proteolytic activities than non-diabetics. This study reveals that M1 and M2 macrophages could differentially modulate major atherosclerosis-related pathological processes. Moreover, M1 macrophages from diabetics display a deleterious phenotype that could explain the higher plaque vulnerability observed in these subjects.


Assuntos
Aterosclerose/genética , Doenças das Artérias Carótidas/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Macrófagos/metabolismo , Neovascularização Patológica/genética , Idoso , Antígenos de Superfície/genética , Aterosclerose/complicações , Aterosclerose/diagnóstico por imagem , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/diagnóstico por imagem , Estudos de Casos e Controles , Moléculas de Adesão Celular Neuronais/genética , Angiografia Cerebral , Angiografia Coronária , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Diabetes Mellitus Tipo 2/complicações , Fator XIII/genética , Feminino , Regulação da Expressão Gênica , Glicoproteínas/genética , Humanos , Interleucina-10/genética , Interleucina-1beta/genética , Lectinas Tipo C/genética , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/genética , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Receptores de Orexina , Fenótipo , Inibidor 1 de Ativador de Plasminogênio/genética , Estudos Prospectivos , Proteólise , Receptores de Superfície Celular/genética , Receptores de Retorno de Linfócitos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inibidor Tecidual de Metaloproteinase-1/genética , Fator de Necrose Tumoral alfa/genética
8.
Nat Rev Cardiol ; 12(1): 10-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25367649

RESUMO

Macrophage accumulation within the vascular wall is a hallmark of atherosclerosis. In atherosclerotic lesions, macrophages respond to various environmental stimuli, such as modified lipids, cytokines, and senescent erythrocytes, which can modify their functional phenotypes. The results of studies on human atherosclerotic plaques demonstrate that the relative proportions of macrophage subsets within a plaque might be a better indicator of plaque phenotype and stability than the total number of macrophages. Understanding the function of specific macrophage subsets and their contribution to the composition and growth of atherosclerotic plaques would aid the identification of novel strategies to delay or halt the development of the disease and its associated pathophysiological consequences. However, most studies aimed at characterizing the phenotypes of human macrophages are performed in vitro and, therefore, their functional relevance to human pathology remains uncertain. In this Review, the diverse range of macrophage phenotypes in atherosclerotic lesions and their potential roles in both plaque progression and stability are discussed, with an emphasis on human pathology.


Assuntos
Aterosclerose/patologia , Macrófagos/patologia , Placa Aterosclerótica/patologia , Citocinas/metabolismo , Progressão da Doença , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Metabolismo dos Lipídeos , Ativação de Macrófagos , Macrófagos/metabolismo
9.
Handb Exp Pharmacol ; 224: 617-30, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25523004

RESUMO

Dyslipidaemia is a major risk factor for cardiovascular diseases. Pharmacological lowering of LDL-C levels using statins reduces cardiovascular risk. However, a substantial residual risk persists especially in patients with type 2 diabetes mellitus. Because of the inverse association observed in epidemiological studies of HDL-C with the risk for cardiovascular diseases, novel therapeutic strategies to raise HDL-C levels or improve HDL functionality are developed as complementary therapy for cardiovascular diseases. However, until now most therapies targeting HDL-C levels failed in clinical trials because of side effects or absence of clinical benefits. This chapter will highlight the emerging small molecules currently developed and tested in clinical trials to pharmacologically modulate HDL-C and functionality including new CETP inhibitors (anacetrapib, evacetrapib), novel PPAR agonists (K-877, CER-002, DSP-8658, INT131 and GFT505), LXR agonists (ATI-111, LXR-623, XL-652) and RVX-208.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Desenho de Fármacos , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Dislipidemias/complicações , Dislipidemias/metabolismo , Humanos , Hipolipemiantes/química , Receptores X do Fígado , Terapia de Alvo Molecular , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Quinazolinas/uso terapêutico , Quinazolinonas , Transdução de Sinais/efeitos dos fármacos
10.
Immunol Rev ; 262(1): 153-66, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25319333

RESUMO

Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype.


Assuntos
Aterosclerose/etiologia , Macrófagos/imunologia , Macrófagos/metabolismo , Fenótipo , Animais , Aterosclerose/patologia , Movimento Celular , Humanos , Ativação de Macrófagos , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Fatores de Transcrição/metabolismo
11.
Circ J ; 78(8): 1775-81, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24998279

RESUMO

Atherosclerosis is the result of a chronic inflammatory response in the arterial wall related to uptake of low-density lipoprotein by macrophages and their subsequent transformation in foam cells. Monocyte-derived macrophages are the principal mediators of tissue homeostasis and repair, response to pathogens and inflammation. However, macrophages are a homogeneous cell population presenting a continuum phenotypic spectrum with, at the extremes, the classically Th-1 polarized M1 and alternatively Th-2 polarized M2 macrophage phenotypes, which have been well described. Moreover, M2 macrophages also present several subtypes often termed M2a, b, c and d, each of them expressing specific markers and exhibiting specialized properties. Macrophage plasticity is mirrored also in the atherosclerotic lesions, where different stimuli can influence the phenotype giving rise to a complex system of subpopulations, such as Mox, Mhem, M(Hb) and M4 macrophages. An abundant literature has described the potential modulators of the reciprocal skewing between pro-inflammatory M1 and anti-inflammatory M2 macrophages including lesion stage and localization, miRNA, transcription factors such as PPARγ, KLF4 and NR4A family members, high-density lipoproteins and plaque lipid content, pathways such as the rapamycin-mTOR1 pathway, molecules such as thioredoxin-1, infection by helminths and irradiation. We hope to provide an overview of the macrophage phenotype complexity in cardiovascular diseases, particularly atherosclerosis.


Assuntos
Aterosclerose/imunologia , Macrófagos/classificação , Macrófagos/imunologia , Animais , Aterosclerose/patologia , Humanos , Fator 4 Semelhante a Kruppel , Lipoproteínas HDL/imunologia , Macrófagos/patologia , MicroRNAs/imunologia , Serina-Treonina Quinases TOR/imunologia , Células Th1/imunologia , Células Th1/patologia , Células Th2/imunologia , Células Th2/patologia , Tiorredoxinas/imunologia , Fatores de Transcrição/imunologia
12.
J Am Soc Nephrol ; 25(11): 2658-68, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24854267

RESUMO

Endothelial dysfunction begins in early CKD and contributes to cardiovascular mortality. HDL is considered antiatherogenic, but may have adverse vascular effects in cardiovascular disease, diabetes, and inflammatory conditions. The effect of renal failure on HDL properties is unknown. We studied the endothelial effects of HDL isolated from 82 children with CKD stages 2-5 (HDL(CKD)), who were free of underlying inflammatory diseases, diabetes, or active infections. Compared with HDL from healthy children, HDL(CKD) strongly inhibited nitric oxide production, promoted superoxide production, and increased vascular cell adhesion molecule-1 expression in human aortic endothelial cells, and reduced cholesterol efflux from macrophages. The effects on endothelial cells correlated with CKD grade, with the most profound changes induced by HDL from patients on dialysis, and partial recovery observed with HDL isolated after kidney transplantation. Furthermore, the in vitro effects on endothelial cells associated with increased aortic pulse wave velocity, carotid intima-media thickness, and circulating markers of endothelial dysfunction in patients. Symmetric dimethylarginine levels were increased in serum and fractions of HDL from children with CKD. In a longitudinal follow-up of eight children undergoing kidney transplantation, HDL-induced production of endothelial nitric oxide, superoxide, and vascular cell adhesion molecule-1 in vitro improved significantly at 3 months after transplantation, but did not reach normal levels. These results suggest that in children with CKD without concomitant disease affecting HDL function, HDL dysfunction begins in early CKD, progressing as renal function declines, and is partially reversed after kidney transplantation.


Assuntos
HDL-Colesterol/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/mortalidade , Doenças Vasculares/sangue , Doenças Vasculares/mortalidade , Adolescente , Arginina/análogos & derivados , Arginina/sangue , Biomarcadores/sangue , Criança , LDL-Colesterol/sangue , Endotélio Vascular/metabolismo , Feminino , Humanos , Transplante de Rim/mortalidade , Masculino , Óxido Nítrico/metabolismo , Diálise Renal/mortalidade , Insuficiência Renal Crônica/cirurgia , Triglicerídeos/sangue , Doenças Vasculares/cirurgia
13.
Biochim Biophys Acta ; 1841(6): 827-35, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24603323

RESUMO

Liver X receptors (LXRα and LXRß) are key transcription factors in cholesterol metabolism that regulate cholesterol biosynthesis/efflux and bile acid metabolism/excretion in the liver and numerous organs. In macrophages, LXR signaling modulates cholesterol handling and the inflammatory response, pathways involved in atherosclerosis. Since regulatory pathways of LXR transcription control are well understood, in the present study we aimed at identifying post-transcriptional regulators of LXR activity. MicroRNAs (miRs) are such post-transcriptional regulators of genes that in the canonical pathway mediate mRNA inactivation. In silico analysis identified miR-206 as a putative regulator of LXRα but not LXRß. Indeed, as recently shown, we found that miR-206 represses LXRα activity and expression of LXRα and its target genes in hepatic cells. Interestingly, miR-206 regulates LXRα differently in macrophages. Stably overexpressing miR-206 in THP-1 human macrophages revealed an up-regulation and miR-206 knockdown led to a down-regulation of LXRα and its target genes. In support of these results, bone marrow-derived macrophages (BMDMs) from miR-206 KO mice also exhibited lower expression of LXRα target genes. The physiological relevance of these findings was proven by gain- and loss-of-function of miR-206; overexpression of miR-206 enhanced cholesterol efflux in human macrophages and knocking out miR-206 decreased cholesterol efflux from MPMs. Moreover, we show that miR-206 expression in macrophages is repressed by LXRα activation, while oxidized LDL and inflammatory stimuli profoundly induced miR-206 expression. We therefore propose a feed-back loop between miR-206 and LXRα that might be part of an LXR auto-regulatory mechanism to fine tune LXR activity.


Assuntos
Colesterol/metabolismo , Metabolismo dos Lipídeos/genética , MicroRNAs/genética , Receptores Nucleares Órfãos/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/patologia , Colesterol/genética , Regulação da Expressão Gênica , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Receptores X do Fígado , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Receptores Nucleares Órfãos/genética , Transdução de Sinais
14.
Int J Cardiol ; 172(1): 179-84, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24456889

RESUMO

BACKGROUND: Macrophages are crucial cells in the pathogenesis of atherosclerosis. Macrophages are plastic cells which can switch from a classical pro-inflammatory M1 to an alternative anti-inflammatory M2 macrophage phenotype, depending on the environmental stimuli. Because high-density lipoprotein (HDL) cholesterol levels are inversely correlated to cardiovascular disease and since HDL displays anti-inflammatory properties, we investigated whether HDL can affect alternative macrophage differentiation of primary human monocytes in the presence of interleukin (IL)-4, a M2 macrophage polarization driver, in vitro and ex vivo. METHODS AND RESULTS: M2 macrophages are highly responsive to HDL stimulation, since the expression of pentraxin 3 (PTX3), a well known HDL target gene, is induced by HDL more strongly in M2 macrophages than in control unpolarized resting macrophages (RM). As expected, the expression of M2 markers, such as Mannose Receptor (MR), CD200 Receptor (CD200R), Coagulation factor XIII A1 (F13A1), IL-1 receptor antagonist (IL-1RA) and IL10, was induced in IL-4 polarized M2 macrophages compared to RM. However, incubation with HDL added in vitro did not modulate the gene expression of M2 macrophage polarization markers. Moreover, monocytes isolated from subjects with genetically low HDL levels, carrying ABCA1 or LCAT mutations, differentiated ex vivo into M2 macrophages without any difference in the alternative macrophage marker expression profile. CONCLUSIONS: These in vitro and ex vivo results indicate that, contrary to mouse macrophages, HDL does not influence macrophage M2 polarization of human monocyte-derived macrophages. Thus, the anti-inflammatory properties of HDL in humans are probably not related to the enhancement of the M2 macrophage phenotype.


Assuntos
Aterosclerose/imunologia , Polaridade Celular/imunologia , HDL-Colesterol/imunologia , Inflamação/imunologia , Monócitos/imunologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/imunologia , Adulto , Antígenos de Superfície/genética , Antígenos de Superfície/imunologia , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores , Células Cultivadas , HDL-Colesterol/farmacologia , Fator XIII/genética , Fator XIII/imunologia , Feminino , Expressão Gênica/imunologia , Humanos , Inflamação/genética , Inflamação/patologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/patologia , Receptores de Orexina , Fenótipo , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Fosfatidilcolina-Esterol O-Aciltransferase/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Adulto Jovem
15.
Biochim Biophys Acta ; 1842(4): 584-93, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24361460

RESUMO

BACKGROUND: Obesity, characterized by low grade inflammation, induces adipose tissue macrophage (ATM) infiltration in white adipose tissue (AT) in both humans and rodents, thus contributing to insulin resistance. Previous studies have shown altered prolactin secretion in obesity, however, studies linking ATM infiltration and prolactin (PRL) secretion to the pathogenesis of the metabolic syndrome, obesity and diabetes are lacking. METHODS/RESULTS: In vivo, qPCR and Western blot analysis demonstrated that prolactin expression was increased in AT of obese rats and also in human AT from obese, obese pre-diabetic and obese diabetic compared to lean counterparts. Immunohistochemistry of obese rat and human AT sections demonstrated a specific expression of prolactin in macrophages. In vitro, we demonstrated that hyperglycemia and inflammation stimulated macrophages (human THP-1 cell line and sorted rat ATM) to express PRL, when challenged with different glucose concentrations with or without IL1ß. In in vivo and in vitro experiments, we assessed the expression of Pit-1 (PRL-specific transcription factor) and found that its expression was parallel to PRL expression. CONCLUSIONS: In this study, we show that rodent and human macrophages synthesize prolactin in response to inflammation and high glucose concentrations. GENERAL SIGNIFICANCE: Our data shed new light on the potential role of macrophages in the physiopathology of diabesity via the PRL expression and on its expression mechanism and regulation.


Assuntos
Tecido Adiposo/fisiologia , Diabetes Mellitus/etiologia , Inflamação/metabolismo , Macrófagos/fisiologia , Obesidade/complicações , Prolactina/fisiologia , Animais , Células Cultivadas , Humanos , Obesidade/sangue , Prolactina/sangue , Ratos , Ratos Wistar , Fator de Transcrição Pit-1/análise
16.
Circ Res ; 113(11): 1196-205, 2013 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-24036496

RESUMO

RATIONALE: In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities. OBJECTIVE: The objective of this study was, first, to better characterize the iron distribution and metabolism in macrophage subpopulations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the liver X receptors (LXRs). METHODS AND RESULTS: Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and mannose receptor (MR)-positive (CD68(+)MR(+)) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favoring iron accumulation. However, M2 macrophages on iron exposure acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extracellular low-density lipoprotein by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68(+)MR(+) macrophages accumulate oxidized lipids, which activate LXRα and LXRß, resulting in the induction of ABCA1, ABCG1, and apolipoprotein E expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 expression, thereby increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export. CONCLUSIONS: These data identify a role for M2 macrophages in iron handling, a process regulated by LXR activation.


Assuntos
Ferro/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Receptores Nucleares Órfãos/fisiologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Apolipoproteínas E/metabolismo , Transporte Biológico/fisiologia , Células Cultivadas , Homeostase/fisiologia , Humanos , Técnicas In Vitro , Lectinas Tipo C/metabolismo , Receptores X do Fígado , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Fenótipo , Receptores de Superfície Celular/metabolismo
18.
Arterioscler Thromb Vasc Biol ; 33(6): 1127-34, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23640494

RESUMO

Macrophages are plastic and versatile cells adapting their function/phenotype to the microenvironment. Distinct macrophage subpopulations with different functions, including classically (M1) and (M2) activated macrophages, have been described. Reciprocal skewing of macrophage polarization between the M1 and M2 state is a process modulated by transcription factors, such as the nuclear peroxisome proliferator-activated receptors. However, whether the estrogen/estrogen receptor pathways control the balance between M1/M2 macrophages is only partially understood. Estrogen-dependent effects on the macrophage system may be regarded as potential targets of pharmacological approaches to protect postmenopausal women from the elevated risk of cardiovascular disease.


Assuntos
Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/fisiopatologia , Estrogênios/metabolismo , Macrófagos/citologia , Macrófagos/imunologia , Comunicação Celular/imunologia , Comunicação Celular/fisiologia , Progressão da Doença , Estrogênios/genética , Feminino , Humanos , Imunidade Inata/fisiologia , Inflamação/imunologia , Inflamação/fisiopatologia , Fenótipo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo
19.
FASEB J ; 27(4): 1519-31, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23303209

RESUMO

11ß-Hydroxysteroid dehydrogenase type-1 (11ß-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11ß-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11ß-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11ß-HSD1 inhibitor or crossed with 11ß-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11ß-HSD1 inhibition or deficiency attenuated atherosclerosis (74-76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11ß-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11ß-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11ß-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/deficiência , Aterosclerose/metabolismo , Medula Óssea/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Aterosclerose/genética , Medula Óssea/efeitos dos fármacos , Glucocorticoides/metabolismo , Camundongos , Camundongos Knockout , Fatores de Risco , Molécula 1 de Adesão de Célula Vascular/metabolismo
20.
Arterioscler Thromb Vasc Biol ; 33(2): 431-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23241402

RESUMO

OBJECTIVE: Abdominal aortic aneurysms (AAAs), dilations of the infrarenal aorta, are characterized by inflammation and oxidative stress. We previously showed increased levels of peroxiredoxin-1 (PRDX-1) in macrophages cultured from AAA patients. The purpose of the study was to determine which subpopulation of macrophages is present in AAAs and is involved in upregulation of PRDX-1 in aneurysmal disease. METHODS AND RESULTS: This study used immunohistochemistry with antibodies against CD68 and mannose receptor (MR) to determine the subtype of macrophages in AAA tissue samples (n=33); laser capture microdissection to isolate each subtype; and quantitative-reverse transcriptase-polymerase chain reaction, Western blot, and ELISA to assess PRDX-1 mRNA and PRDX-1protein levels in both types. Proinflammatory CD68(+)MR(-) macrophages predominated in adventitial tissue, whereas the intraluminal thrombus contained CD68(+)MR(+) macrophages. The presence of lipids and iron-containing deposits confirmed their phagocytic phenotype. Laser capture microdissection-isolated CD68(+)MR(-) and CD68(+)MR(+) macrophages, characterized by quantitative-reverse transcriptase-polymerase chain reaction (TNF, IL1B, MRC1, and CCL18) and Western blot (stabilin and hemoglobin), validated the microdissected subtypes. PRDX-1 expression was colocalized with CD68(+)MR(-) macrophages. PRDX-1 mRNA and PRDX-1 protein were both more abundant in CD68(+)MR(-) than CD68(+)MR(+) macrophages in AAA. CONCLUSIONS: These findings suggest that the proteins or mRNAs expressed by the proinflammatory CD68(+)MR(-) macrophages may contribute to aneurysmal pathology.


Assuntos
Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/enzimologia , Mediadores da Inflamação/análise , Macrófagos/enzimologia , Peroxirredoxinas/metabolismo , Aorta Abdominal/imunologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/patologia , Biomarcadores/análise , Western Blotting , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Regulação Enzimológica da Expressão Gênica , Humanos , Imuno-Histoquímica , Microdissecção e Captura a Laser , Macrófagos/imunologia , Macrófagos/patologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Peroxirredoxinas/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
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