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1.
FASEB J ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924185

RESUMO

Atherosclerosis is an inflammatory disease characterized by the accumulation of macrophages in the vessel wall. Macrophages depend on their polarization to exert either pro-inflammatory or anti-inflammatory effects. Macrophages of the anti-inflammatory phenotype express high levels of CD163, a scavenger receptor for the hemoglobin-haptoglobin complex. CD163 can also bind to the pro-inflammatory cytokine TWEAK. Using ApoE-deficient or ApoE/CD163 double-deficient mice we aim to investigate the involvement of CD163 in atherosclerosis development and its capacity to neutralize the TWEAK actions. ApoE/CD163 double-deficient mice displayed a more unstable plaque phenotype characterized by an increased lipid and macrophage content, plaque size, and pro-inflammatory cytokine expression. In vitro experiments demonstrated that the absence of CD163 in M2-type macrophages-induced foam cell formation through upregulation of CD36 expression. Moreover, exogenous TWEAK administration increased atherosclerotic lesion size, lipids, and macrophages content in ApoE-/- /CD163-/- compared with ApoE-/- /CD163+/+ mice. Treatment with recombinant CD163 was able to neutralize the proatherogenic effects of TWEAK in ApoE/CD163 double-deficient mice. Recombinant CD163 abolished the pro-inflammatory actions of TWEAK on vascular smooth muscle cells, decreasing NF-kB activation, cytokines and metalloproteinases expression, and macrophages migration. In conclusion, CD163-expressing macrophages serve as a protective mechanism to prevent the deleterious effects of TWEAK on atherosclerotic plaque development and progression.

2.
Cells ; 9(2)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32053869

RESUMO

Cardiovascular diseases (CVD) are the leading cause of mortality in Western countries. CVD include several pathologies, such as coronary artery disease, stroke, peripheral artery disease, and aortic aneurysm, among others. All of them are characterized by a pathological vascular remodeling in which inflammation plays a key role. Interaction between different members of the tumor necrosis factor superfamily and their cognate receptors induce several biological actions that may participate in CVD. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its functional receptor, fibroblast growth factor-inducible 14 (Fn14), are abundantly expressed during pathological cardiovascular remodeling. The TWEAK/Fn14 axis controls a variety of cellular functions, such as proliferation, differentiation, and apoptosis, and has several biological functions, such as inflammation and fibrosis that are linked to CVD. It has been demonstrated that persistent TWEAK/Fn14 activation is involved in both vessel and heart remodeling associated with acute and chronic CVD. In this review, we summarized the role of the TWEAK/Fn14 axis during pathological cardiovascular remodeling, highlighting the cellular components and the signaling pathways that are involved in these processes.

3.
EBioMedicine ; 46: 274-289, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31395500

RESUMO

BACKGROUND: Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12; TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Tnfrsf12a; Fn14) participate in the inflammatory response associated with vascular remodeling. However, the functional effect of TWEAK on vascular smooth muscle cells (VSMCs) is not completely elucidated. METHODS: Next generation sequencing-based methods were performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwell migration assays were used to analyze VSMCs proliferation and migration. Mouse wire injury model was done to evaluate the role of TWEAK/Fn14 during neointimal hyperplasia. FINDINGS: TWEAK up-regulated 1611 and down-regulated 1091 genes in VSMCs. Using a gene-set enrichment method, we found a functional module involved in cell proliferation defined as the minimal network connecting top TWEAK up-regulated genes. In vitro experiments in wild-type or Tnfrsf12a deficient VSMCs demonstrated that TWEAK increased cell proliferation, VSMCs motility and migration. Mechanistically, TWEAK increased cyclins (cyclinD1), cyclin-dependent kinases (CDK4, CDK6) and decreased cyclin-dependent kinase inhibitors (p15lNK4B) mRNA and protein expression. Downregulation of p15INK4B induced by TWEAK was mediated by mitogen-activated protein kinase ERK and Akt activation. Tnfrsf12a or Tnfsf12 genetic depletion and pharmacological intervention with TWEAK blocking antibody reduced neointimal formation, decreasing cell proliferation, cyclin D1 and CDK4/6 expression, and increasing p15INK4B expression compared with wild type or IgG-treated mice in wire-injured femoral arteries. Finally, immunohistochemistry in human coronary arteries with stenosis or in-stent restenosis revealed high levels of Fn14, TWEAK and PCNA in VSMCs enriched areas of the neointima as compared with healthy coronary arteries. INTERPRETATION: Our data define a major role of TWEAK/Fn14 in the control of VSMCs proliferation and migration during neointimal hyperplasia after wire injury in mice, and identify TWEAK/Fn14 as a potential target for treating in-stent restenosis. FUND: ISCiii-FEDER, CIBERCV and CIBERDEM.


Assuntos
Angioplastia/efeitos adversos , Reestenose Coronária/etiologia , Reestenose Coronária/metabolismo , Citocina TWEAK/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor de TWEAK/metabolismo , Animais , Biomarcadores , Movimento Celular , Proliferação de Células , Reestenose Coronária/patologia , Modelos Animais de Doenças , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Modelos Biológicos , Miócitos de Músculo Liso/metabolismo , Complicações Pós-Operatórias , Túnica Íntima/metabolismo , Túnica Íntima/patologia
4.
Atherosclerosis ; 270: 13-20, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29407881

RESUMO

BACKGROUND AND AIMS: Vascular calcification (VC) and atherosclerosis are associated with an increased cardiovascular morbimortality in chronic kidney disease (CKD). Osteoprotegerin (OPG) and osteopontin (OPN) are involved in both VC and CKD. Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) has been related to cardiovascular disease. We hypothesized that OPG, OPN and sTWEAK levels may be associated with a higher prevalence of cardiovascular outcomes in patients with CKD. METHODS: The presence of calcified or non-calcified atherosclerotic plaques was assessed in 1043 stage 3 to 5D CKD patients from The NEFRONA Study. Biochemical measurements and OPG, OPN and sTWEAK serum levels were analyzed. Patients were followed for cardiovascular outcomes (41 ±â€¯16 months). RESULTS: At recruitment, 26% of CKD patients had VC. The adjusted odds ratios for having VC were 2.22 (1.32-3.75); p=.003 for OPG, and 0.45 (0.24-0.84); p=.01 for sTWEAK concentrations. After follow-up, 95 CV events occurred. In a Cox model, patients with OPG or OPN above and sTWEAK below their optimal cut-off points had an adjusted higher risk of cardiovascular events [HR: 2.10 (1.49-3.90); p=.02; 1.65 (1.02-2.65); p=.04; 2.05 (1.28-3.29), p=.003; respectively]. When CKD patients were grouped according to the number of biomarkers above (OPG and OPN) or below (sTWEAK) their cut-off points, the combination of these biomarkers showed the highest risk for cardiovascular events [HR: 9.46 (3.80-23.5) p < .001]. A composite score of these three biomarkers increased the C-statistic and net reclassification index beyond conventional risk factors and VC. CONCLUSIONS: The combination of OPG, OPN and sTWEAK increased the predictability of cardiovascular outcomes.


Assuntos
Doenças Cardiovasculares/sangue , Citocina TWEAK/sangue , Osteopontina/sangue , Osteoprotegerina/sangue , Insuficiência Renal Crônica/sangue , Calcificação Vascular/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Prognóstico , Estudos Prospectivos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Medição de Risco , Fatores de Risco , Espanha/epidemiologia , Fatores de Tempo , Calcificação Vascular/diagnóstico , Calcificação Vascular/mortalidade
5.
Atherosclerosis ; 260: 130-137, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28390291

RESUMO

BACKGROUND AND AIMS: Circulating soluble TNF-like weak inducer of apoptosis (sTWEAK) concentrations are related to the presence of chronic kidney disease (CKD) and cardiovascular disease (CVD). However, there are no data regarding the potential association between sTWEAK and atheromatosis progression in patients free of cardiovascular events. METHODS: Soluble TWEAK serum concentration was measured in 702 CKD patients without any previous CV event from The National Observatory of Atherosclerosis in Nephrology (NEFRONA) Study. B-mode ultrasound was performed to detect the presence of carotid and/or femoral atherosclerotic plaques. The association between sTWEAK levels, atherosclerotic burden (number of plaques) and atheromatosis progression (increase in the number of plaques) after 24 months of follow-up was analyzed. RESULTS: A continuous decrease in sTWEAK concentrations, with an increase in the number of atherosclerotic plaques after 24 months of follow-up, was observed in the studied population. Multivariable linear regression analysis showed that age, blood pressure, HDL-c, and sTWEAK concentrations were independent predictors of atherosclerotic burden after 24 months of follow-up. In addition, sTWEAK concentrations diminished in CKD patients in whom progressive silent atherosclerosis was observed. Multivariable linear regression analysis showed that age, sex, smoking status and sTWEAK levels were independent predictors of atheromatosis progression after 24 months of follow-up. CONCLUSIONS: Lower sTWEAK concentrations are associated with atherosclerotic burden and atheromatosis progression in CKD patients free of clinical CVD. These data suggest that sTWEAK could serve as a biomarker to predict CV risk before clinical manifestations.


Assuntos
Citocina TWEAK/sangue , Placa Aterosclerótica/sangue , Insuficiência Renal Crônica/complicações , Adolescente , Adulto , Idoso , Índice Tornozelo-Braço , Apoptose , Biomarcadores/sangue , Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Progressão da Doença , Feminino , Artéria Femoral/diagnóstico por imagem , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/diagnóstico , Placa Aterosclerótica/etiologia , Prognóstico , Insuficiência Renal Crônica/sangue , Adulto Jovem
6.
Sci Rep ; 7: 46679, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28447667

RESUMO

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK/Tnfsf12) is a cytokine implicated in different steps associated with vascular remodeling. However, the role of TWEAK under hyperglycemic conditions is currently unknown. Using two different approaches, genetic deletion of Tnfsf12 and treatment with a TWEAK blocking mAb, we have analyzed the effect of TWEAK inhibition on atherosclerotic plaque progression and stability in streptozotocin-induced diabetic ApoE deficient mice. Genetic inactivation of Tnfsf12 reduced atherosclerosis extension and severity in diabetic ApoE deficient mice. Tnfsf12 deficient mice display a more stable plaque phenotype characterized by lower lipid and macrophage content within atherosclerotic plaques. A similar phenotype was observed in diabetic mice treated with anti-TWEAK mAb. The proatherosclerotic effects of TWEAK were mediated, at least in part, by STAT1 activation and expression of proinflammatory target genes (CCL5, CXCL10 and ICAM-1), both in plaques of ApoE mice and in cultured vascular smooth muscle cells (VSMCs) under hyperglycemic conditions. Loss-of-function experiments demonstrated that TWEAK induces proinflammatory genes mRNA expression through its receptor Fn14 and STAT1 activation in cultured VSMCs. Overall, TWEAK blockade delay plaque progression and alter plaque composition in diabetic atherosclerotic mice. Therapies aimed to inhibit TWEAK expression and/or function could protect from diabetic vascular complications.


Assuntos
Aterosclerose/metabolismo , Citocina TWEAK/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fator de Transcrição STAT1/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/genética , Aterosclerose/prevenção & controle , Células Cultivadas , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Citocina TWEAK/genética , Citocina TWEAK/imunologia , Diabetes Mellitus Experimental/genética , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Camundongos Knockout , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/prevenção & controle , Fator de Transcrição STAT1/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia
7.
Cardiovasc Res ; 111(3): 262-73, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27229458

RESUMO

AIMS: To study the role of lipocalin-2 (Lcn2) and the effect of Lcn2 blockade via anti-Lcn2 antibody in the development of abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Expression mRNA and protein levels of Lcn2 and its human orthologue neutrophil gelatinase-associated lipocalin (NGAL) in aortic wall samples from experimental mouse and human AAA samples, respectively, were analysed by real-time PCR and immunohistochemistry. Experimental AAA was induced by aortic elastase perfusion in wild-type mice (WT) and Lcn2-deficient mice (Lcn2-/-). NGAL/Lcn2 mRNA and protein levels in human and murine AAA samples were increased compared with healthy aortas. Decreased AAA incidence and reduced aortic expansion were observed in Lcn2-/- mice or mice preoperative treated with a polyclonal anti-Lcn2 antibody compared with WT mice or mice treated with control IgG, respectively, at Day 14 after elastase perfusion. Moreover, immunohistochemical analysis of AAA tissues from Lcn2-/- or anti-Lcn2-treated mice showed diminished elastin damage, reduced microvessels and polymorphonuclear neutrophil (PMN) infiltration, and enhanced preservation of vascular smooth muscle cells compared with WT aortas. Fluorescent molecular tomography revealed decreased MMP activity in AAA of Lcn2-/- mice compared with WT controls. Therapeutic administration of anti-Lcn2 antibody to WT mice 3 days after elastase perfusion decreased aortic dilatation and PMN infiltration compared with WT mice treated with control IgG. CONCLUSION: Either Lcn2 deficiency or anti-Lcn2 antibody blockade limits AAA expansion in mice by decreasing PMN infiltration in the aorta. Lcn2 modulation may therefore be a viable new therapeutic option for the treatment of AAA.


Assuntos
Anticorpos/farmacologia , Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/prevenção & controle , Lipocalina-2/antagonistas & inibidores , Lipocalina-2/deficiência , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Estudos de Casos e Controles , Células Cultivadas , Quimiotaxia de Leucócito/efeitos dos fármacos , Dilatação Patológica , Modelos Animais de Doenças , Elastina/metabolismo , Predisposição Genética para Doença , Humanos , Lipocalina-2/genética , Lipocalina-2/imunologia , Lipocalina-2/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/patologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Infiltração de Neutrófilos/efeitos dos fármacos , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Tempo
8.
Clin J Am Soc Nephrol ; 11(3): 413-22, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-26728587

RESUMO

BACKGROUND AND OBJECTIVES: Soluble TNF-like weak inducer of apoptosis (sTWEAK) is a proinflammatory cytokine belonging to the TNF superfamily. sTWEAK concentrations have been associated with the presence of CKD and cardiovascular disease (CVD). We hypothesized that sTWEAK levels may relate to a higher prevalence of atherosclerotic plaques, vascular calcification, and cardiovascular outcomes observed in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 4-year prospective, multicenter, longitudinal study was conducted in 1058 patients with CKD stages 3-5D (mean age =58±13 years old; 665 men) but without any history of CVD from the NEFRONA Study (a study design on the prevalence of surrogate markers of CVD). Ankle-brachial index and B-mode ultrasound were performed to detect the presence of carotid and/or femoral atherosclerotic plaques together with biochemical measurements and sTWEAK assessment. Patients were followed for cardiovascular outcomes (follow-up of 3.13±1.15 years). RESULTS: Patients with more advanced CKD had lower sTWEAK levels. sTWEAK concentrations were independently and negatively associated with carotid intima-media thickness. sTWEAK levels were lower in patients with carotid atherosclerotic plaques but not in those with femoral plaques. After adjustment by confounders, the odds ratio (OR) for presenting carotid atherosclerotic plaques in patients in the lowest versus highest tertile of sTWEAK was 4.18 (95% confidence interval [95% CI], 2.89 to 6.08; P<0.001). Furthermore, sTWEAK levels were lower in patients with calcified carotid atherosclerotic plaques. The OR for presenting calcified carotid plaques was 1.77 (95% CI, 1.06 to 2.93; P=0.02) after multivariable adjustment. After the follow-up, 41 fatal and 68 nonfatal cardiovascular events occurred. In a Cox model, after controlling for potential confounding factors, patients in the lowest tertile of sTWEAK concentrations had a higher risk of fatal and nonfatal cardiovascular events (hazard ratio [HR], 2.40; 95% CI, 1.33 to 4.33; P=0.004) and cardiovascular mortality (HR, 2.67; 95% CI, 1.05 to 6.76; P=0.04). CONCLUSIONS: Low sTWEAK levels were associated with the presence of carotid atherosclerotic plaques in patients with CKD. Additionally, lower sTWEAK levels were associated with a higher risk of cardiovascular morbidity and mortality.


Assuntos
Doenças das Artérias Carótidas/etiologia , Artéria Femoral , Doença Arterial Periférica/etiologia , Insuficiência Renal Crônica/sangue , Fatores de Necrose Tumoral/sangue , Calcificação Vascular/etiologia , Idoso , Índice Tornozelo-Braço , Biomarcadores/sangue , Doenças das Artérias Carótidas/diagnóstico , Doenças das Artérias Carótidas/mortalidade , Espessura Intima-Media Carotídea , Distribuição de Qui-Quadrado , Citocina TWEAK , Regulação para Baixo , Feminino , Artéria Femoral/diagnóstico por imagem , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/mortalidade , Placa Aterosclerótica , Prevalência , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Fatores de Risco , Espanha/epidemiologia , Fatores de Tempo , Calcificação Vascular/diagnóstico , Calcificação Vascular/mortalidade
9.
Atherosclerosis ; 239(2): 358-63, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25681674

RESUMO

OBJECTIVE: Reduced soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) levels have been related with cardiovascular disease. However, there are no data on the relationship between sTWEAK and atherosclerotic burden in subjects with or without cardiovascular risk factors but free from clinical disease. We have analyzed the association between circulating sTWEAK levels and the presence of carotid and/or femoral atherosclerotic plaques in subjects without known vascular disease. METHODS: A multicenter, cross-sectional study was conducted in 448 subjects free from clinical CVD. B-mode ultrasound was performed to detect the presence of carotid and/or femoral atherosclerotic plaques. sTWEAK concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: sTWEAK serum levels were reduced in parallel with an increment in cardiovascular risk factors. sTWEAK concentrations were independently and negatively associated with carotid intima/media thickness. Subjects with atherosclerotic plaques showed a reduction in sTWEAK levels [808 (645-963) vs 993 (830-1278); p < 0.001]. A gradual decrease in sTWEAK levels was observed as the number of atherosclerotic plaques increased in our studied population. When we analyzed sTWEAK levels according to the vascular territory affected, we observed that sTWEAK concentrations were only diminished in subjects with carotid atherosclerotic plaques but not in those with femoral plaques. Following adjustment for various confounders, the OR for presenting carotid atherosclerotic plaque in subjects in lower vs higher tertile of sTWEAK levels was 8.09 [4.30-15.23; median (IQR); p < 0.001]. CONCLUSIONS: Diminished sTWEAK concentrations were significantly and independently associated with the presence of carotid atherosclerotic plaques in asymptomatic subjects.


Assuntos
Artérias Carótidas/fisiopatologia , Regulação da Expressão Gênica , Placa Aterosclerótica/sangue , Fatores de Necrose Tumoral/sangue , Adolescente , Adulto , Idoso , Aterosclerose/fisiopatologia , Biomarcadores/sangue , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , Estudos Transversais , Citocina TWEAK , Feminino , Artéria Femoral/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários
10.
Clín. investig. arterioscler. (Ed. impr.) ; 27(1): 17-25, ene.-feb. 2015. ilus
Artigo em Espanhol | IBECS | ID: ibc-131379

RESUMO

Objetivos: La interacción del factor inductor débil de apoptosis similar al factor de necrosis tumoral (TWEAK) con su receptor Fn14 acelera el desarrollo de la lesión aterosclerótica en ratones deficientes en ApoE (ApoE KO). En este trabajo hemos analizado el efecto de un inhibidor de la HMG-CoA reductasa, la atorvastatina, sobre el desarrollo de la lesión aterosclerótica acelerada por TWEAK en ratones ApoE KO. Materiales y métodos: Se alimentaron ratones ApoE KO de 8 semanas de edad durante 4 semanas con una dieta hiperlipidémica y se aleatorizaron en 3 grupos: ratones tratados i.p. con salino (control), tratados con TWEAK recombinante (10 μg/kg/2 veces a la semana) o tratados con TWEAK recombinante más atorvastatina (1 mg/kg/día) durante 4 semanas más. Se analizó el tamaño, la composición celular, la respuesta inflamatoria y la expresión de Fn14 en las lesiones ateroscleróticas presentes en la raíz aórtica de los ratones. Resultados: La inyección sistémica de TWEAK aumentó el tamaño de la lesión y el cociente colágeno/lípidos así como la respuesta inflamatoria asociada a un aumento en la actividad de NF-κB, expresión de MCP-1 y RANTES y a una mayor presencia de macrófagos en las placas ateroscleróticas de ratones ApoE KO. El tratamiento con atorvastatina fue capaz de prevenir los cambios inducidos por TWEAK en las lesiones ateroscleróticas. Finalmente, el tratamiento con atorvastatina disminuyó la expresión de Fn14 en las lesiones ateroscleróticas de ratones ApoE KO. Conclusiones: La atorvastatina previene los efectos proaterogénicos inducidos por TWEAK en el ratón ApoE KO, efecto relacionado con la inhibición de la expresión de Fn14. Estos resultados aportan nueva información sobre los efectos beneficiosos de las estatinas en el tratamiento de las enfermedades cardiovasculares


Aim: Interaction of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) with its receptor Fn14 accelerates atherosclerotic plaque development in ApoE deficient mice (ApoE KO). In this work, an analysis has been made on the effect of an HMG-CoA reductase inhibitor, atorvastatin, on atherosclerotic plaque development accelerated by TWEAK in ApoE KO mice. Materials and methods: Eight week-old ApoE KO mice were fed with a high cholesterol diet for 4 weeks. The animals were then randomized into 3 groups: mice injected i.p. with saline, recombinant TWEAK (10 μg/kg/twice a week), or recombinant TWEAK plus atorvastat in (1 mg/kg/day) for 4 weeks. The lesion size, cellular composition, lipid and collagen content were analyzed, as well as inflammatory response in atherosclerotic plaques present in aortic root of mice. Results: TWEAK treated mice showed an increase in atherosclerotic plaque size, as well as in collagen/lipid ratio compared with control mice. In addition, macrophage content, MCP-1 and RANTES expression, and NF-κB activation were augmented in atherosclerotic plaques present in aortic root of TWEAK treated mice compared with control mice. Treatment with atorvastatin prevented all these changes induced by TWEAK in atherosclerotic lesions. Atorvastatin treatment also decreased Fn14 expression in the atherosclerotic plaques of ApoE KO mice. Conclusions: Atorvastatin prevents the pro-atherogenic effects induced by TWEAK in ApoE KO mice, which could be related to the inhibition of Fn14 expression. The results of this study provide new information on the beneficial effects of statin treatment in cardiovascular diseases


Assuntos
Animais , Camundongos , Anticolesterolemiantes/farmacocinética , Aterosclerose/tratamento farmacológico , Fator de Indução de Apoptose , Progressão da Doença , Inflamação/fisiopatologia , Modelos Animais de Doenças , Apolipoproteínas E/deficiência
11.
Clin Investig Arterioscler ; 27(1): 17-25, 2015.
Artigo em Espanhol | MEDLINE | ID: mdl-25027757

RESUMO

AIM: Interaction of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) with its receptor Fn14 accelerates atherosclerotic plaque development in ApoE deficient mice (ApoE KO). In this work, an analysis has been made on the effect of an HMG-CoA reductase inhibitor, atorvastatin, on atherosclerotic plaque development accelerated by TWEAK in ApoE KO mice. MATERIALS AND METHODS: Eight week-old ApoE KO mice were fed with a high cholesterol diet for 4 weeks. The animals were then randomized into 3 groups: mice injected i.p. with saline, recombinant TWEAK (10 µg/kg/twice a week), or recombinant TWEAK plus atorvastatin (1 mg/kg/day) for 4 weeks. The lesion size, cellular composition, lipid and collagen content were analyzed, as well as inflammatory response in atherosclerotic plaques present in aortic root of mice. RESULTS: TWEAK treated mice showed an increase in atherosclerotic plaque size, as well as in collagen/lipid ratio compared with control mice. In addition, macrophage content, MCP-1 and RANTES expression, and NF-κB activation were augmented in atherosclerotic plaques present in aortic root of TWEAK treated mice compared with control mice. Treatment with atorvastatin prevented all these changes induced by TWEAK in atherosclerotic lesions. Atorvastatin treatment also decreased Fn14 expression in the atherosclerotic plaques of ApoE KO mice. CONCLUSIONS: Atorvastatin prevents the pro-atherogenic effects induced by TWEAK in ApoE KO mice, which could be related to the inhibition of Fn14 expression. The results of this study provide new information on the beneficial effects of statin treatment in cardiovascular diseases.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/prevenção & controle , Atorvastatina/farmacologia , Fatores de Necrose Tumoral/metabolismo , Animais , Aorta/patologia , Aterosclerose/patologia , Citocina TWEAK , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Placa Aterosclerótica/patologia , Placa Aterosclerótica/prevenção & controle , Receptores do Fator de Necrose Tumoral/metabolismo , Receptor de TWEAK , Fatores de Necrose Tumoral/administração & dosagem
12.
J Am Heart Assoc ; 3(4)2014 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-25092786

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) involves leukocyte recruitment, inflammatory cytokine production, vascular cell apoptosis, neovascularization, and vascular remodeling, all of which contribute to aortic dilatation. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a cytokine implicated in proinflammatory responses, angiogenesis, and matrix degradation but its role in AAA formation is currently unknown. METHODS AND RESULTS: Experimental AAA with aortic elastase perfusion in mice was induced in wild-type (WT), TWEAK deficient (TWEAK KO), or Fn14-deficient (Fn14 KO) mice. TWEAK or Fn14 KO deficiency reduced aortic expansion, lesion macrophages, CD3(+) T cells, neutrophils, CD31(+) microvessels, CCL2 and CCL5 chemokines expression, and MMP activity after 14 days postperfusion. TWEAK and Fn14 KO mice also showed a reduced loss of medial vascular smooth muscle cells (VSMC) that was related to a reduced number of apoptotic cells in these animals compared with WT mice. Aortas from WT animals present a higher disruption of the elastic layer and MMP activity than those from TWEAK or Fn14 KO mice, indicating a diminished vascular remodeling in KO animals. In vitro experiments unveiled that TWEAK induces CCL5 secretion and MMP-9 activation in both VSMC and bone marrow-derived macrophages, and decrease VSMC viability, effects dependent on Fn14. CONCLUSIONS: TWEAK/Fn14 axis participates in AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, matrix-degrading protease expression, and vascular remodeling. Blocking TWEAK/Fn14 interaction could be a new target for the treatment of AAA.


Assuntos
Aneurisma da Aorta Abdominal/genética , Receptores do Fator de Necrose Tumoral/genética , Fatores de Necrose Tumoral/genética , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/imunologia , Apoptose/genética , Apoptose/imunologia , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Quimiocina CCL5/imunologia , Quimiocina CCL5/metabolismo , Citocina TWEAK , Modelos Animais de Doenças , Inflamação , Macrófagos/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neutrófilos/imunologia , Elastase Pancreática/toxicidade , Receptores do Fator de Necrose Tumoral/imunologia , Receptores do Fator de Necrose Tumoral/metabolismo , Linfócitos T/imunologia , Receptor de TWEAK , Fatores de Necrose Tumoral/imunologia , Fatores de Necrose Tumoral/metabolismo
13.
PLoS One ; 9(3): e90541, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24594990

RESUMO

BACKGROUND: Patients infected with the human immunodeficiency virus (HIV) have an increased risk of cardiovascular disease due to increased inflammation and persistent immune activation. CD163 is a macrophage scavenger receptor that is involved in monocyte-macrophage activation in HIV-infected patients. CD163 interacts with TWEAK, a member of the TNF superfamily. Circulating levels of sTWEAK and sCD163 have been previously associated with cardiovascular disease, but no previous studies have fully analyzed their association with HIV. OBJECTIVE: The aim of this study was to analyze circulating levels of sTWEAK and sCD163 as well as other known markers of inflammation (hsCRP, IL-6 and sTNFRII) and endothelial dysfunction (sVCAM-1 and ADMA) in 26 patients with HIV before and after 48 weeks of antiretroviral treatment (ART) and 23 healthy subjects. RESULTS: Patients with HIV had reduced sTWEAK levels and increased sCD163, sVCAM-1, ADMA, hsCRP, IL-6 and sTNFRII plasma concentrations, as well as increased sCD163/sTWEAK ratio, compared with healthy subjects. Antiretroviral treatment significantly reduced the concentrations of sCD163, sVCAM-1, hsCRP and sTNFRII, although they remained elevated when compared with healthy subjects. Antiretroviral treatment had no effect on the concentrations of ADMA and sTWEAK, biomarkers associated with endothelial function. The use of protease inhibitors as part of antiretroviral therapy and the presence of HCV-HIV co-infection and/or active HIV replication attenuated the ART-mediated decrease in sCD163 plasma concentrations. CONCLUSION: HIV-infected patients showed a proatherogenic profile characterized by increased inflammatory, immune-activation and endothelial-dysfunction biomarkers that partially improved after ART. HCV-HIV co-infection and/or active HIV replication enhanced immune activation despite ART.


Assuntos
Antirretrovirais/uso terapêutico , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Coinfecção/sangue , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Hepatite C/sangue , Receptores de Superfície Celular/sangue , Fatores de Necrose Tumoral/sangue , Adulto , Arginina/análogos & derivados , Arginina/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Coinfecção/tratamento farmacológico , Citocina TWEAK , Feminino , HIV/efeitos dos fármacos , HIV/isolamento & purificação , Hepacivirus/isolamento & purificação , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Molécula 1 de Adesão de Célula Vascular/sangue , Adulto Jovem
14.
Ann Vasc Surg ; 28(7): 1642-8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24632318

RESUMO

BACKGROUND: Abdominal aortic aneurysms (AAAs) are currently followed with serial ultrasound or computed tomography scanning diameter measurements, but evidence shows that AAA expansion is mostly discontinuous and quite unpredictable in any given patient. A reliable predictive model of AAA growth and/or rupture risk could help individualize treatment, follow-up protocols, and cost-effectiveness. Our objective is to set a predictive model of short-term prospective AAA growth, after clinical, serologic, and anatomic data. METHODS: A prospective pilot cohort was designed. We recruited 96 consecutive, asymptomatic, infrarenal, atherosclerotic AAA patients. We registered clinical data (age, gender, cardiovascular risk factors, comorbidity, and statin intake), baseline aortic diameter, prospective 1-year AAA growth, and the concentration of metalloprotease-2, metalloprotease-9, cystatin C, α1-antitrypsin, myeloperoxidase, monocyte chemoattractant protein-1, homocysteine, D-dimer, plasmin-antiplasmin complex (PAP), and C-reactive protein in peripheral blood at the time of baseline assessment. With all these data, we elaborated predictive models for 1-year AAA growth assessed both as a continuous variable (mm/year) and a dichotomic one (defined as stability, if AAA growth rate was ≤2 mm/year, versus expansion, if AAA growth rate was >2 mm/year), using simple and multiple linear and logistic regression. RESULTS: The multivariate model confirmed the independent impact of D-dimer levels and chronic renal failure (CRF) on increasing AAA growth rates. Every increase by 1 ng/mL in the plasma concentration of D-dimer was related to a mean 1-year increase of 0.0062 mm in the AAA growth. Likewise, CRF increased the 1-year prospective AAA growth by a mean of 2.95 mm. When we assessed AAA growth as a dichotomic variable, the increase in the peripheral concentrations of PAP slightly increased the risk of AAA expansion (odds ratio [OR]: 1.01; 95% confidence interval [CI]: 1.00-1.02), but the presence of CRF increased the risk dramatically (OR: 14,523.62; 95% CI: 0-7.39E+40). CONCLUSIONS: Plasma D-dimer and PAP levels seem promising biomarkers of short-term AAA activity. CRF is an important independent prognostic factor of AAA expansion. The dichotomic classification of AAA growth, as stability versus progression, can be useful in the development of management models and their clinical application.


Assuntos
Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/patologia , Biomarcadores/sangue , Idoso , Comorbidade , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Projetos Piloto , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco
15.
J Cell Mol Med ; 18(4): 721-34, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24479820

RESUMO

Clinical complications associated with atherosclerotic plaques arise from luminal obstruction due to plaque growth or destabilization leading to rupture. Tumour necrosis factor ligand superfamily member 12 (TNFSF12) also known as TNF-related weak inducer of apoptosis (TWEAK) is a proinflammatory cytokine that participates in atherosclerotic plaque development, but its role in plaque stability remains unclear. Using two different approaches, genetic deletion of TNFSF12 and treatment with a TWEAK blocking mAb in atherosclerosis-prone mice, we have analysed the effect of TWEAK inhibition on atherosclerotic plaques progression and stability. Mice lacking both TNFSF12 and Apolipoprotein E (TNFSF12(-/-) ApoE(-/-) ) exhibited a diminished atherosclerotic burden and lesion size in their aorta. Advanced atherosclerotic plaques of TNFSF12(-/-) ApoE(-/-) or anti-TWEAK treated mice exhibited an increase collagen/lipid and vascular smooth muscle cell/macrophage ratios compared with TNFSF12(+/+) ApoE(-/-) control mice, reflecting a more stable plaque phenotype. These changes are related with two different mechanisms, reduction of the inflammatory response (chemokines expression and secretion and nuclear factor kappa B activation) and decrease of metalloproteinase activity in atherosclerotic plaques of TNFSF12(-/-) ApoE(-/-) . A similar phenotype was observed with anti-TWEAK mAb treatment in TNFSF12(+/+) ApoE(-/-) mice. Brachiocephalic arteries were also examined since they exhibit additional features akin to human atherosclerotic plaques associated with instability and rupture. Features of greater plaque stability including augmented collagen/lipid ratio, reduced macrophage content, and less presence of lateral xanthomas, buried caps, medial erosion, intraplaque haemorrhage and calcium content were present in TNFSF12(-/-) ApoE(-/-) or anti-TWEAK treatment in TNFSF12(+/+) ApoE(-/-) mice. Overall, our data indicate that anti-TWEAK treatment has the capacity to diminish proinflamatory response associated with atherosclerotic plaque progression and to alter plaque morphology towards a stable phenotype.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Aterosclerose/genética , Placa Aterosclerótica/genética , Fatores de Necrose Tumoral/genética , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/genética , Apoptose/genética , Apoptose/imunologia , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Aterosclerose/patologia , Citocina TWEAK , Humanos , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/patologia , Inibidores do Fator de Necrose Tumoral , Fatores de Necrose Tumoral/imunologia
16.
Front Immunol ; 5: 3, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24478772

RESUMO

Cardiovascular diseases (CVD) are the first cause of mortality in Western countries. CVD include several pathologies such as coronary heart disease, stroke or cerebrovascular accident, congestive heart failure, peripheral arterial disease, and aortic aneurysm, among others. Interaction between members of the tumor necrosis factor (TNF) superfamily and their receptors elicits several biological actions that could participate in CVD. TNF-like weak inducer of apoptosis (TWEAK) and its functional receptor and fibroblast growth factor-inducible molecule 14 (Fn14) are two proteins belonging to the TNF superfamily that activate NF-κB by both canonical and non-canonical pathways and regulate several cell functions such as proliferation, migration, differentiation, cell death, inflammation, and angiogenesis. TWEAK/Fn14 axis plays a beneficial role in tissue repair after acute injury. However, persistent TWEAK/Fn14 activation mediated by blocking experiments or overexpression experiments in animal models has shown an important role of this axis in the pathological remodeling underlying CVD. In this review, we summarize the role of TWEAK/Fn14 pathway in the development of CVD, focusing on atherosclerosis and stroke and the molecular mechanisms by which TWEAK/Fn14 interaction participates in these pathologies. We also review the role of the soluble form of TWEAK as a biomarker for the diagnosis and prognosis of CVD. Finally, we highlight the results obtained with other members of the TNF superfamily that also activate canonical and non-canonical NF-κB pathway.

17.
Eur J Clin Invest ; 43(12): 1250-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24112080

RESUMO

BACKGROUND: Soluble TWEAK (sTWEAK) and asymmetric dimethyl arginine (ADMA) concentrations have been associated with endothelial function in patients with chronic kidney disease (CKD). We tested the hypothesis that the improvement in endothelial function observed after renal transplantation is directly linked to the normalization of both sTWEAK and ADMA. MATERIALS AND METHODS: One hundred and seventy-five kidney transplant recipients (71% men; 31·6 ± 9·4 years) were studied immediately before and on the 180th day post-transplantation. At each visit, blood samples were taken to assess circulating levels of sTWEAK and ADMA. Brachial artery endothelium-dependent vasodilatation (FMD) assessments were also performed. RESULTS: Renal transplantation was followed by an improvement in FMD. This improvement was paralleled by an increase in sTWEAK and a reduction in ADMA after transplantation (P < 0·001 for all). Cross-sectionally, both molecules associated with FMD before as well as after transplantation (P < 0·001 for all). Longitudinally, the changes observed in sTWEAK (ß = 0·26, P < 0·001) and ADMA (ß = -0·44, P < 0·001) levels were independently associated with the improvement of FMD (r(2)  = 0·30). CONCLUSIONS: Renal transplantation is followed by an improvement of FMD that is independently associated with the normalization of both sTWEAK and ADMA concentrations. We identify two surrogate biomarkers of endothelial function with potential as therapeutic targets.


Assuntos
Arginina/análogos & derivados , Endotélio Vascular/fisiologia , Transplante de Rim , Insuficiência Renal Crônica/sangue , Fatores de Necrose Tumoral/metabolismo , Adulto , Arginina/metabolismo , Biomarcadores/metabolismo , Artéria Braquial/fisiologia , Proteína C-Reativa/fisiologia , Citocina TWEAK , Feminino , Humanos , Masculino , Período Pós-Operatório , Estudos Prospectivos , Insuficiência Renal Crônica/cirurgia , Doenças Vasculares/sangue , Doenças Vasculares/fisiopatologia , Vasodilatação/fisiologia
18.
Arterioscler Thromb Vasc Biol ; 33(8): 2013-20, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23702661

RESUMO

OBJECTIVE: To identify proteins related to intraluminal thrombus biological activities that could help to find novel pathological mechanisms and therapeutic targets for human abdominal aortic aneurysm (AAA). APPROACH AND RESULTS: Tissue-conditioned media from patients with AAA were analyzed by a mass spectrometry-based strategy using liquid chromatography coupled to tandem mass spectrometry. Global pathway analysis by Ingenuity software highlighted the presence of several circulating proteins, among them were proteins from the complement system. Complement C3 concentration and activation were assessed in plasma from AAA patients (small AAA, AAA diameter=3-5 cm and large AAA, AAA diameter >5 cm), showing decreased C3 levels and activation in large AAA patients. No association of a combination of single-nucleotide polymorphisms in complement genes between large and small AAA patients was observed. Intense extracellular C3 inmunostaining, along with C9, was observed in AAA thrombus. Analysis of C3 in AAA tissue homogenates and tissue-conditioned media showed increased levels of C3 in AAA thrombus, as well as proteolytic fragments (C3a/C3c/C3dg), suggesting its local deposition and activation. Finally, the functional role of local complement activation in polymorphonuclear (PMN) cell activation was tested, showing that C3 blockade by anti-C3 antibody was able to decrease thrombus-induced neutrophil chemotaxis and reactive oxygen species production. CONCLUSIONS: A decrease of systemic C3 concentration and activity in the later stages of AAA associated with local complement retention, consumption, and proteolysis in the thrombus could induce PMN chemotaxis and activation, playing a detrimental role in AAA progression.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Proteômica/métodos , Trombose/metabolismo , Trombose/patologia , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/epidemiologia , Autoanticorpos/metabolismo , Quimiotaxia/fisiologia , Cromatografia Líquida/métodos , Complemento C3/genética , Complemento C3/metabolismo , Complemento C9/genética , Complemento C9/metabolismo , Meios de Cultivo Condicionados/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Neutrófilos/metabolismo , Polimorfismo de Nucleotídeo Único , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco , Espectrometria de Massas em Tandem/métodos , Trombose/epidemiologia
19.
Methods Mol Biol ; 1000: 91-101, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23585087

RESUMO

In the search for novel biomarkers, noncandidate-based proteomic strategies open up new opportunities to gain a deeper insight into disease processes regarding their molecular mechanisms, the risk factors involved, and the monitoring of disease progression. To carry out these complex analyses, the combined use of gel electrophoresis with mass spectrometry (MS) represents a powerful choice. In addition, the introduction of protein dye labeling has notably improved the reliability of differential expression studies by increasing the statistical significance of the protein candidates. Here, we describe a strategy where different layers (luminal/abluminal) from the intraluminal thrombus (ILT) of human abdominal aortic aneurysm (AAA) patients were incubated in protein-free medium. Then, the levels of the proteins released were compared by two-dimensional differential in-gel electrophoresis (2D-DIGE) and the proteins of interest identified by MS. We consider that the use of tissue-conditioned media could offer a substantial advantage in the analytical study of biological fluids, as they provide a source of proteins to be released to the bloodstream, which could serve as potential circulating biomarkers.


Assuntos
Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/metabolismo , Meios de Cultivo Condicionados , Eletroforese em Gel Bidimensional/métodos , Proteômica/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Trombose/patologia , Biomarcadores/metabolismo , Mineração de Dados , Bases de Dados de Proteínas , Humanos , Proteólise , Coloração pela Prata , Trombose/complicações , Tripsina/metabolismo
20.
J Nephrol ; 26(6): 1105-13, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23475462

RESUMO

BACKGROUND: Chronic kidney disease (CKD) is characterized by a high mortality rate, primarily due to cardiovascular disease. Reduced soluble TNF-like weak inducer of apoptosis (sTWEAK) levels have been related with endothelial function in CKD patients. However, there are no data on the relationship between sTWEAK and its scavenger receptor CD163 and atherosclerotic burden in CKD. METHODS: A cross-sectional, observational study was conducted in 58 patients with CKD stages 1-3, 86 with CKD stages 4-5, 195 on dialysis and 86 healthy controls. The severity of atherosclerosis was estimated with the atherosclerosis score (AS), combining the results of ankle-brachial index and carotid ultrasound. sTWEAK and CD163 plasma concentrations were measured by ELISA. RESULTS: sTWEAK plasma levels were diminished and CD163 concentrations were increased in patients with CKD compared with controls (sTWEAK: median [interquartile range] 308 pg/mL [258-378] vs. 371 pg/mL [319-455]; p<0.001; and CD163: 1,047 ng/mL [740-1,495] vs. 540 ng/mL [319-765]; p<0.001; respectively). A weak but statistically significant association between sTWEAK or CD163 and carotid intima-media thickness (r = -0.109, p = 0.025; r = 0.179, p<0.001; respectively) was observed. Patients with more severe atherosclerosis presented a higher reduction in sTWEAK concentrations (312 pg/mL [302-322] vs. 368 pg/mL [351-385]; p<0.001) and a higher increment in CD163 levels (1,182 ng/mL [1,107-1,258] vs. 826 ng/mL [733-919]; p<0.001). After multivariable analysis, only elevated sTWEAK levels were associated with reduced risk of atherosclerosis (0.34 [0.14-0.86], p = 0.02). CONCLUSIONS: A significant reduction in sTWEAK and increment in CD163 plasma levels were observed in patients with more severe atherosclerosis. Our results indicate that sTWEAK could be a novel biomarker of atherosclerotic burden in CKD patients.


Assuntos
Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Aterosclerose/sangue , Receptores de Superfície Celular/sangue , Insuficiência Renal Crônica/sangue , Fatores de Necrose Tumoral/sangue , Adulto , Idoso , Índice Tornozelo-Braço , Aterosclerose/complicações , Aterosclerose/patologia , Biomarcadores/sangue , Doenças das Artérias Carótidas/diagnóstico por imagem , Estudos de Casos e Controles , Estudos Transversais , Citocina TWEAK , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Ultrassonografia
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