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1.
Basic Res Cardiol ; 114(1): 1, 2018 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-30443679

RESUMEN

Monocytes are involved in adverse left ventricular (LV) remodelling following myocardial infarction (MI). To provide therapeutic opportunities we aimed to identify gene transcripts in monocytes that relate to post-MI healing and evaluated intervention with the observed gene activity in a rat MI model. In 51 MI patients treated by primary percutaneous coronary intervention (PCI), the change in LV end-diastolic volume index (EDVi) from baseline to 4-month follow-up was assessed using cardiovascular magnetic resonance imaging (CMR). Circulating monocytes were collected at day 5 (Arterioscler Thromb Vasc Biol 35:1066-1070, 2015; Cell Stem Cell 16:477-487, 2015; Curr Med Chem 13:1877-1893, 2006) after primary PCI for transcriptome analysis. Transcriptional profiling and pathway analysis revealed that patients with a decreased LV EDVi showed an induction of type I interferon (IFN) signalling (type I IFN pathway: P value < 0.001; false discovery rate < 0.001). We subsequently administered 15,000 Units of IFN-α subcutaneously in a rat MI model for three consecutive days following MI. Cardiac function was measured using echocardiography and infarct size/cardiac inflammation using (immuno)-histochemical analysis. We found that IFN-α application deteriorated ventricular dilatation and increased infarct size at day 28 post-MI. Moreover, IFN-α changed the peripheral monocyte subset distribution towards the pro-inflammatory monocyte subset whereas in the myocardium, the presence of the alternative macrophage subset was increased at day 3 post-MI. Our findings suggest that induction of type I IFN signalling in human monocytes coincides with adverse LV remodelling. In rats, however, IFN-α administration deteriorated post-MI healing. These findings underscore important but also contradictory roles for the type I IFN response during cardiac healing following MI.


Asunto(s)
Interferón Tipo I/metabolismo , Monocitos/trasplante , Infarto del Miocardio/metabolismo , Infarto del Miocardio/terapia , Remodelación Ventricular , Adulto , Anciano , Animales , Trasplante de Médula Ósea/métodos , Femenino , Humanos , Interferón Tipo I/farmacología , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Infarto del Miocardio/patología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Remodelación Ventricular/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/fisiología
2.
Cancer Invest ; 36(7): 371-377, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30188739

RESUMEN

We examined if serum concentrations Interferon gamma-induced protein (IP-10) is a potential clinical biomarker for cancer-related-fatigue (CRF). Fatigue scores and IP-10 concentrations were measured from curatively treated fatigued cancer patients randomized to either cognitive behavioral therapy (CBT, n = 26) or waiting-list (WL, n = 13). No correlation was found between baseline IP-10 level and fatigue severity and no significant differences in IP-10 serum levels were observed between fatigued and matched non-fatigued patients (n = 22). Relative changes in IP-10 concentrations from baseline to six-month follow-up were not significantly different between the CBT and WL conditions. In this study, IP-10 showed low potential as clinical CRF biomarker. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT01096641).


Asunto(s)
Quimiocina CXCL10/sangre , Fatiga/sangre , Neoplasias/complicaciones , Adulto , Biomarcadores/sangre , Terapia Cognitivo-Conductual , Estudios Transversales , Fatiga/diagnóstico , Fatiga/etiología , Fatiga/terapia , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento
3.
J Am Heart Assoc ; 6(3)2017 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-28275068

RESUMEN

BACKGROUND: In order to identify factors that stimulate arteriogenesis after ischemia, we followed gene expression profiles in two extreme models for collateral artery formation over 28 days after hindlimb ischemia, namely "good-responding" C57BL/6 mice and "poor-responding" BALB/c mice. METHODS AND RESULTS: Although BALB/c mice show very poor blood flow recovery after ischemia, most known proarteriogenic genes were upregulated more excessively and for a longer period than in C57BL/6 mice. In clear contrast, chemokine genes Ccl19, Ccl21a, and Ccl21c and the chemokine receptor CCR7 were upregulated in C57BL/6 mice 1 day after hindlimb ischemia, but not in BALB/C mice. CCL19 and CCL21 regulate migration and homing of T lymphocytes via CCR7. When subjecting CCR7-/-/LDLR-/- mice to hindlimb ischemia, we observed a 20% reduction in blood flow recovery compared with that in LDLR-/- mice. Equal numbers of α-smooth muscle actin-positive collateral arteries were found in the adductor muscles of both mouse strains, but collateral diameters were smaller in the CCR7-/-/LDLR-/-. Fluorescence-activated cell sorter analyses showed that numbers of CCR7+ T lymphocytes (both CD4+ and CD8+) were decreased in the spleen and increased in the blood at day 1 after hindlimb ischemia in LDLR-/- mice. At day 1 after hindlimb ischemia, however, numbers of activated CD4+ T lymphocytes were decreased in the draining lymph nodes of LDLR-/- mice compared with CCR7-/-/LDLR-/- mice. CONCLUSIONS: These data show that CCR7-CCL19/CCL21 axis facilitates retention CD4+ T lymphocytes at the site of collateral artery remodeling, which is essential for effective arteriogenesis.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Quimiocina CCL19/genética , Quimiocina CCL21/genética , Circulación Colateral/genética , Miembro Posterior/irrigación sanguínea , Isquemia/genética , Neovascularización Fisiológica/genética , Receptores CCR7/genética , Animales , Circulación Colateral/inmunología , Expresión Génica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Fisiológica/inmunología , Receptores de LDL/genética , Regulación hacia Arriba
4.
Angiogenesis ; 20(1): 39-54, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27699500

RESUMEN

During prolonged hypoxic conditions, endothelial cells change their gene expression to adjust to the low oxygen environment. This process is mainly regulated by the hypoxia-inducible factors, HIF-1α and HIF-2α. Although endothelial cells do not form sprouts during prolonged hypoxic culturing, silencing of HIF-2α partially restores sprout formation. The present study identifies novel HIF-2α-target genes that may regulate endothelial sprouting during prolonged hypoxia. The gene expression profile of primary human microvascular endothelial cells (hMVECs) that were cultured at 20 % oxygen was compared to hMVECs that were cultured at 1 % oxygen for 14 days by using genome-wide RNA-sequencing. The differentially regulated genes in hypoxia were compared to the genes that were differentially regulated upon silencing of HIF-2α in hypoxia. Surprisingly, KEGG pathway analysis showed that metabolic pathways were enriched within genes upregulated in response to hypoxia and enriched within genes downregulated upon HIF-2α silencing. Moreover, 51 HIF-2α-regulated genes were screened for their role in endothelial sprouting in hypoxia, of which four genes ARRDC3, MME, PPARG and RALGPS2 directly influenced endothelial sprouting during prolonged hypoxic culturing. The manipulation of specific downstream targets of HIF-2α provides a new, but to be further evaluated, perspective for restoring reduced neovascularization in several pathological conditions, such as diabetic ulcers or other chronic wounds, for improvement of vascularization of implanted tissue-engineered scaffolds.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Endoteliales/metabolismo , Regulación de la Expresión Génica , Microvasos/citología , Neovascularización Fisiológica/genética , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/genética , Células Endoteliales/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Humanos , Oxígeno/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transfección
5.
Vascul Pharmacol ; 81: 31-41, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26945624

RESUMEN

Galectins are an ancient family of ß-galactoside-specific lectins and consist of 15 different types, each with a specific function. They play a role in the immune system, inflammation, wound healing and carcinogenesis. In particular the role of galectin in cancer is widely studied. Lately, the role of galectins in the development of cardiovascular disease has gained attention. Worldwide cardiovascular disease is still the leading cause of death. In ischemic heart disease, atherosclerosis limits adequate blood flow. Angiogenesis and arteriogenesis are highly important mechanisms relieving ischemia by restoring perfusion to the post-stenotic myocardial area. Galectins act ambiguous, both relieving ischemia and accelerating atherosclerosis. Atherosclerosis can ultimately lead to myocardial infarction or ischemic stroke, which are both associated with galectins. There is also a role for galectins in the development of myocarditis by their influence on inflammatory processes. Moreover, galectin acts as a biomarker for the severity of myocardial ischemia and heart failure. This review summarizes the association between galectins and the development of multiple cardiovascular diseases such as myocarditis, ischemic stroke, myocardial infarction, heart failure and atrial fibrillation. Furthermore it focuses on the association between galectin and more general mechanisms such as angiogenesis, arteriogenesis and atherosclerosis.


Asunto(s)
Enfermedades Cardiovasculares/metabolismo , Galectinas/metabolismo , Animales , Biomarcadores/metabolismo , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/fisiopatología , Humanos , Neovascularización Patológica , Neovascularización Fisiológica , Valor Predictivo de las Pruebas , Pronóstico , Índice de Severidad de la Enfermedad , Transducción de Señal
6.
Arthritis Res Ther ; 18: 49, 2016 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-26882897

RESUMEN

BACKGROUND: Activation of the type I interferon (IFN) response program is described for several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), myositis (IIM) and rheumatoid arthritis (RA). While IFNα contributes to SLE pathology, IFNß therapy is often beneficial in MS, implying different immunoregulatory roles for these IFNs. This study was aimed to investigate potential diversification of IFNα-and IFNß-mediated response programs in autoimmune diseases. METHODS: Peripheral blood gene expression of 23 prototypical type I IFN response genes (IRGs) was determined in 54 healthy controls (HCs), 69 SLE (47 test, 22 validation), 149 IFNß-treated MS (71 test, 78 validation), 160 untreated MS, 78 IIM and 76 RA patients. Patients with a type I IFN signature were selected for analysis. RESULTS: We identified IFNα- and IFNß-specific response programs (GC-A and GC-B, respectively) in SLE and IFNß-treated MS patients. Concordantly, the GC-A/GC-B log-ratio was positive for all SLE patients and negative for virtually all IFNß-treated MS patients, which was confirmed in additional cohorts. Applying this information to other autoimmune diseases, IIM patients displayed positive GC-A/GC-B log-ratios, indicating predominant IFNα activity. The GC-A/GC-B log-ratio in RA was lower and approached zero in part of the patients, implying relative importance of both clusters. Remarkably, GC-A/GC-B log-ratios appeared most heterogeneous in untreated MS; half of the patients displayed GC-A dominance, whereas others showed GC-B dominance or log-ratios near zero. CONCLUSIONS: Our findings show diversification of the type I IFN response in autoimmune diseases, suggesting different pathogenic roles of the type I IFNs.


Asunto(s)
Interferón-alfa/uso terapéutico , Interferón beta/uso terapéutico , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/tratamiento farmacológico , Esclerosis Múltiple/sangre , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Anciano , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Femenino , Humanos , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Resultado del Tratamiento
7.
PLoS One ; 10(12): e0145777, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26717516

RESUMEN

The flow-responsive transcription factor Krüppel-like factor 2 (KLF2) maintains an anti-coagulant, anti-inflammatory endothelium with sufficient nitric oxide (NO)-bioavailability. In this study, we aimed to explore, both in vitro and in human vascular tissue, expression of the NO-transporting transmembrane pore aquaporin-1 (AQP1) and its regulation by atheroprotective KLF2 and atherogenic inflammatory stimuli. In silico analysis of gene expression profiles from studies that assessed the effects of KLF2 overexpression in vitro and atherosclerosis in vivo on endothelial cells, identifies AQP1 as KLF2 downstream gene with elevated expression in the plaque-free vessel wall. Biomechanical and pharmaceutical induction of KLF2 in vitro is accompanied by induction of AQP1. Chromosome immunoprecipitation (CHIP) confirms binding of KLF2 to the AQP1 promoter. Inflammatory stimulation of endothelial cells leads to repression of AQP1 transcription, which is restrained by KLF2 overexpression. Immunohistochemistry reveals expression of aquaporin-1 in non-activated endothelium overlying macrophage-poor intimae, irrespective whether these intimae are characterized as being plaque-free or as containing advanced plaque. We conclude that AQP1 expression is subject to KLF2-mediated positive regulation by atheroprotective shear stress and is downregulated under inflammatory conditions both in vitro and in vivo. Thus, endothelial expression of AQP1 characterizes the atheroprotected, non-inflamed vessel wall. Our data provide support for a continuous role of KLF2 in stabilizing the vessel wall via co-temporal expression of eNOS and AQP1 both preceding and during the pathogenesis of atherosclerosis.


Asunto(s)
Acuaporina 1/metabolismo , Endotelio Vascular/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Óxido Nítrico/metabolismo , Acuaporina 1/genética , Transporte Biológico/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inmunohistoquímica , Mediadores de Inflamación/farmacología , Factores de Transcripción de Tipo Kruppel/genética , Placa Aterosclerótica/patología , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Unión Proteica/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estrés Mecánico , Transcripción Genética/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología
8.
Am J Physiol Heart Circ Physiol ; 309(10): H1667-78, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26432845

RESUMEN

Circulating angiogenic cells (CACs) are monocyte-derived cells with endothelial characteristics, which contribute to both angiogenesis and arteriogenesis in a paracrine way. Interferon-ß (IFN-ß) is known to inhibit these divergent processes in animals and patients. We hypothesized that IFN-ß might act by affecting the differentiation and function of CACs. CACs were cultured from peripheral blood mononuclear cells and phenotypically characterized by surface expression of monocytic and endothelial markers. IFN-ß significantly reduced the number of CACs by 18-64%. Apoptosis was not induced by IFN-ß, neither in mononuclear cells during differentiation, nor after maturation to CACs. Rather, IFN-ß impaired adhesion to, and spreading on, fibronectin, which was dependent on α5ß1 (VLA-5)-integrin. IFN-ß affected the function of VLA-5 in mature CACs, leading to rounding and detachment of cells, by induction of calpain 1 activity. Cell rounding and detachment was completely reversed by inhibition of calpain 1 activity in mature CACs. During in vitro capillary formation, CAC addition and calpain 1 inhibition enhanced sprouting of endothelial cells to a comparable extent, but were not sufficient to rescue tube formation in the presence of IFN-ß. We show that the IFN-ß-induced reduction of the numbers of in vitro differentiated CACs is based on activation of calpain 1, resulting in an attenuated adhesion to extracellular matrix proteins via VLA-5. In vivo, this could lead to inhibition of vessel formation due to reduction of the locally recruited CAC numbers and their paracrine angiogenic factors.


Asunto(s)
Calpaína/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Interferón beta/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Apoptosis/efectos de los fármacos , Calpaína/metabolismo , Células Cultivadas , Células Endoteliales/metabolismo , Fibronectinas , Humanos , Técnicas In Vitro , Integrina alfa5beta1/efectos de los fármacos , Integrina alfa5beta1/metabolismo , Leucocitos Mononucleares/metabolismo , Neovascularización Fisiológica/fisiología
9.
Vascul Pharmacol ; 75: 7-18, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26254104

RESUMEN

A defect in neo-vascularization process involving circulating angiogenic mononuclear cells (CACs) dysfunction is associated with diabetes. We showed that oxidative stress was elevated in CACs cultured from blood of individuals with metabolic syndrome (MetS) and diabetes. We then assessed the action of palmitic acid (PA), a deregulated and increased NEFA in metabolic disorders, focusing on its oxidant potential. We observed that the phyto-polyphenol resveratrol normalized oxidative stress both in CACs isolated from MetS patients or treated with PA. Resveratrol further decreased the deleterious action of PA on gene expression of vascularization factors (TNFα, VEGF-A, SDF1α, PECAM-1, VEGFR2, Tie2 and CXCR4) and improved CAC motility. Particularly, resveratrol abolished the PA-induced over-expression of the pro-oxidant protein p66Shc. Neither KLF2 nor SIRT1, previously shown in resveratrol and p66Shc action, was directly involved. Silencing p66Shc normalized PA action on VEGF-A and TNFα specifically, without abolishing the PA-induced oxidative stress, which suggests a deleterious role of p66Shc independently of any major modulation of the cellular oxidative status in a high NEFA levels context. Besides showing that resveratrol reverses PA-induced harmful effects on human CAC function, certainly through profound cellular modifications, we establish p66Shc as a major therapeutic target in metabolic disorders, independent from glycemic control.


Asunto(s)
Estrés Oxidativo/efectos de los fármacos , Ácido Palmítico/metabolismo , Proteínas Adaptadoras de la Señalización Shc/genética , Estilbenos/farmacología , Antioxidantes/farmacología , Estudios de Casos y Controles , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Diabetes Mellitus Tipo 2/fisiopatología , Regulación de la Expresión Génica/efectos de los fármacos , Silenciador del Gen , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Neovascularización Fisiológica/efectos de los fármacos , Resveratrol , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src
10.
BMC Med Genomics ; 8: 20, 2015 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-25956355

RESUMEN

BACKGROUND: Metabolic syndrome (MetS) is characterized by central obesity, insulin resistance, dysglycemia, and a pro-atherogenic plasma lipid profile. MetS creates a high risk for development of type 2 diabetes (T2DM) and cardiovascular disease (CVD), presumably by altering inflammatory responses. Presently, it is unknown how the chronic metabolic disturbances in acute hyperglycemia, MetS and T2DM affect the immune activity of peripheral blood cells. METHODS: We performed genome-wide expression analysis of peripheral blood cells obtained from patients with T2DM (n = 6) and age-, sex- , BMI- and blood pressure-matched obese individuals with MetS (n = 4) and lean healthy normoglycemic controls (n = 3), both under fasting conditions and after controlled induction of acute hyperglycemia during a 70 min hyperglycemic clamp. Differential gene expression during fasting conditions was confirmed by real-time PCR, for which we included additional age-, sex-, BMI-, and blood pressure-matched obese individuals with (n = 4) or without (n = 4) MetS. RESULTS: Pathway and Gene ontology analysis applied to baseline expression profiles of peripheral blood cells from MetS and T2DM patients revealed metabolic changes, highly similar to a reoviral infection gene signature in T2DM patients. Transcription factor binding site analysis indicated that increased HIF-1α activity, a transcription factor induced by either hypoxia or oxidative stress, is responsible for this aberrant metabolic profile in peripheral blood cells from T2DM patients. Acute hyperglycemia in healthy controls resulted in reduced expression of cytotoxicity-related genes, representing NK- and CD8(+) cells. In obese controls, MetS and especially T2DM patients, baseline expression of genes involved in cytotoxicity was already low, compared to healthy controls and did not further decrease upon acute hyperglycemia. CONCLUSIONS: The reduced activity of cytotoxic genes in T2DM is explained by chronic hyperglycemia, but its acute effects are restricted to healthy controls. Genome expression of circulating leukocytes from T2DM patients differs from MetS individuals by a specific reovirus signature. Our data thus suggest a role for suppressed anti-viral capacity in the etiology of diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Síndrome Metabólico/sangre , Reoviridae/genética , Anciano , Presión Sanguínea , Índice de Masa Corporal , Enfermedades Cardiovasculares/metabolismo , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/virología , Femenino , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Técnica de Clampeo de la Glucosa , Humanos , Inflamación/metabolismo , Lípidos/sangre , Masculino , Síndrome Metabólico/genética , Persona de Mediana Edad , Obesidad Abdominal/genética , Obesidad Abdominal/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos
11.
Cardiovasc Res ; 107(2): 255-66, 2015 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-25935869

RESUMEN

AIMS: IFN-beta (IFNß) signalling is increased in patients with insufficient coronary collateral growth (i.e. arteriogenesis) and IFNß hampers arteriogenesis in mice. A downside of most pro-arteriogenic agents investigated in the past has been their pro-atherosclerotic properties, rendering them unsuitable for therapeutic application. Interestingly, type I IFNs have also been identified as pro-atherosclerotic cytokines and IFNß treatment increases plaque formation and accumulation of macrophages. We therefore hypothesized that mAb therapy to inhibit IFNß signalling would stimulate arteriogenesis and simultaneously attenuate-rather than aggravate-atherosclerosis. METHODS AND RESULTS: In a murine hindlimb ischaemia model, atherosclerotic low-density lipoprotein receptor knockout (LDLR(-/-)) mice were treated during a 4-week period with blocking MAbs specific for mouse IFN-α/ß receptor subunit 1 (IFNAR1) or murine IgG isotype as a control. The arteriogenic response was quantified using laser Doppler perfusion imaging (LDPI) as well as immunohistochemistry. Effects on atherosclerosis were determined by quantification of plaque area and analysis of plaque composition. Downstream targets of IFNß were assessed by real-time PCR (RT-PCR) in the aortic arch. Hindlimb perfusion restoration after femoral artery ligation was improved in mice treated with anti-IFNAR1 compared with controls as assessed by LDPI. This was accompanied by a decrease in CXCL10 expression in the IFNAR1 MAb-treated group. Anti-IFNAR1 treatment reduced plaque apoptosis without affecting total plaque area or other general plaque composition parameters. Results were confirmed in a short-term model and in apolipoprotein E knockout (APOE)(-/-) mice. CONCLUSION: Monoclonal anti-IFNAR1 therapy during a 4-week treatment period stimulates collateral artery growth in mice and did not enhance atherosclerotic burden. This is the first reported successful strategy using MAbs to stimulate arteriogenesis.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Arteria Femoral/inmunología , Miembro Posterior/efectos de los fármacos , Miembro Posterior/inmunología , Isquemia/tratamiento farmacológico , Receptor de Interferón alfa y beta/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Aterosclerosis/metabolismo , Circulación Colateral/efectos de los fármacos , Modelos Animales de Enfermedad , Arteria Femoral/fisiología , Miembro Posterior/irrigación sanguínea , Isquemia/inmunología , Isquemia/metabolismo , Macrófagos/inmunología , Ratones Noqueados , Monocitos/metabolismo
12.
PLoS One ; 10(4): e0124347, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25884209

RESUMEN

Galectin-2 is a monocyte-expressed carbohydrate-binding lectin, for which increased expression is genetically determined and associated with decreased collateral arteriogenesis in obstructive coronary artery disease patients. The inhibiting effect of galectin-2 on arteriogenesis was confirmed in vivo, but the mechanism is largely unknown. In this study we aimed to explore the effects of galectin-2 on monocyte/macrophage phenotype in vitro and vivo, and to identify the receptor by which galectin-2 exerts these effects. We now show that the binding of galectin-2 to different circulating human monocyte subsets is dependent on monocyte surface expression levels of CD14. The high affinity binding is blocked by an anti-CD14 antibody but not by carbohydrates, indicating a specific protein-protein interaction. Galectin-2 binding to human monocytes modulated their transcriptome by inducing proinflammatory cytokines and inhibiting pro-arteriogenic factors, while attenuating monocyte migration. Using specific knock-out mice, we show that galectin-2 acts through the CD14/toll-like receptor (TLR)-4 pathway. Furthermore, galectin-2 skews human macrophages to a M1-like proinflammatory phenotype, characterized by a reduced motility and expression of an anti-arteriogenic cytokine/growth factor repertoire. This is accompanied by a switch in surface protein expression to CD40-high and CD206-low (M1). In a murine model we show that galectin-2 administration, known to attenuate arteriogenesis, leads to increased numbers of CD40-positive (M1) and reduced numbers of CD206-positive (M2) macrophages surrounding actively remodeling collateral arteries. In conclusion galectin-2 is the first endogenous CD14/TLR4 ligand that induces a proinflammatory, non-arteriogenic phenotype in monocytes/macrophages. Interference with CD14-Galectin-2 interaction may provide a new intervention strategy to stimulate growth of collateral arteries in genetically compromised cardiovascular patients.


Asunto(s)
Circulación Colateral/fisiología , Galectina 2/fisiología , Inflamación/fisiopatología , Macrófagos/fisiología , Monocitos/fisiología , Animales , Antígenos CD40/biosíntesis , Diferenciación Celular , Células Cultivadas , Circulación Colateral/efectos de los fármacos , Células Dendríticas/metabolismo , Galectina 2/deficiencia , Galectina 2/genética , Galectina 2/farmacología , Regulación de la Expresión Génica , Humanos , Lectinas Tipo C/biosíntesis , Receptores de Lipopolisacáridos/inmunología , Receptores de Lipopolisacáridos/fisiología , Macrófagos/clasificación , Macrófagos/efectos de los fármacos , Receptor de Manosa , Lectinas de Unión a Manosa/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/efectos de los fármacos , Fenotipo , Unión Proteica/efectos de los fármacos , Células RAW 264.7 , Receptores de Superficie Celular/biosíntesis , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Transducción de Señal , Linfocitos T/metabolismo , Receptor Toll-Like 4/metabolismo
13.
J Interferon Cytokine Res ; 35(6): 411-20, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25714660

RESUMEN

In this review we discuss the current literature on the effects of type I interferons (IFN) and their downstream effectors on vascular growth in experimental models in vitro and in vivo. In addition to its well-documented role in angiogenesis, that is, the growth of new capillaries from existing vessels, we will also describe emerging evidence and mechanisms by which type I IFN may inhibit arteriogenesis, that is, the expansive remodeling of existing collateral arteries. Crucial in both processes is the common role of circulating monocytes, which are known to act as pivotal cellular modulators in revascularization through secreted chemokines, proteases, and growth factors. These secreted molecules, which are all modulated by IFN signaling, act via degradation of the extracellular matrix and by stimulating the proliferation of vascular smooth muscle cells and endothelial cells. Thus, next to the antiviral and immunomodulatory activities of type I IFNs, a potent role of IFN-ß as modulator of revascularization is now emerging and may be considered a potential clinical target for the stimulation of angiogenesis and arteriogenesis in ill-perfused tissues.


Asunto(s)
Estenosis de la Válvula Aórtica/metabolismo , Interferón beta/farmacología , Morfogénesis/efectos de los fármacos , Isquemia Miocárdica/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Animales , Estenosis de la Válvula Aórtica/inmunología , Estenosis de la Válvula Aórtica/patología , Arterias/citología , Arterias/efectos de los fármacos , Arterias/inmunología , Proliferación Celular/efectos de los fármacos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/inmunología , Matriz Extracelular/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Péptidos y Proteínas de Señalización Intercelular/farmacología , Interferón beta/genética , Interferón beta/inmunología , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/inmunología , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/inmunología , Isquemia Miocárdica/inmunología , Isquemia Miocárdica/patología , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/inmunología
14.
J Mol Cell Cardiol ; 67: 94-102, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24389343

RESUMEN

Acute myocardial infarction (AMI) is accompanied by increased expression of Toll like receptors (TLR)-2 and TLR4 on circulating monocytes. In animal models, blocking TLR2/4 signaling reduces inflammatory cell influx and infarct size. The clinical consequences of TLR activation during AMI in humans are unknown, including its role in long-term cardiac functional outcome Therefore, we analyzed gene expression in whole blood samples from 28 patients with an acute ST elevation myocardial infarction (STEMI), enrolled in the EXenatide trial for AMI patients (EXAMI), both at admission and after 4-month follow-up, by whole genome expression profiling and real-time PCR. Cardiac function was determined by cardiac magnetic resonance (CMR) imaging at baseline and after 4-month follow-up. TLR pathway activation was shown by increased expression of TLR4 and its downstream genes, including IL-18R1, IL-18R2, IL-8, MMP9, HIF1A, and NFKBIA. In contrast, expression of the classical TLR-induced genes, TNF, was reduced. Bioinformatics analysis and in vitro experiments explained this noncanonical TLR response by identification of a pivotal role for HIF-1α. The extent of TLR activation and IL-18R1/2 expression in circulating cells preceded massive troponin-T release and correlated with the CMR-measured ischemic area (R=0.48, p=0.01). In conclusion, we identified a novel HIF-1-dependent noncanonical TLR activation pathway in circulating leukocytes leading to enhanced IL-18R expression which correlated with the magnitude of the ischemic area. This knowledge may contribute to our mechanistic understanding of the involvement of the innate immune system during STEMI and may yield diagnostic and prognostic value for patients with myocardial infarction.


Asunto(s)
Interleucina-18/metabolismo , Infarto del Miocardio/fisiopatología , Receptor Toll-Like 4/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Interleucina-18/sangre , Interleucina-18/genética , Leucocitos/metabolismo , Persona de Mediana Edad , Receptor Toll-Like 4/sangre , Receptor Toll-Like 4/genética , Regulación hacia Arriba
15.
Arterioscler Thromb Vasc Biol ; 33(8): 1902-10, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23788761

RESUMEN

OBJECTIVE: Therapeutic arteriogenesis, that is, expansive remodeling of preexisting collaterals, using single-action factor therapies has not been as successful as anticipated. Modulation of factors that act as a master switch for relevant gene programs may prove more effective. Transcriptional coactivator p300-CBP-associated factor (PCAF) has histone acetylating activity and promotes transcription of multiple inflammatory genes. Because arteriogenesis is an inflammation-driven process, we hypothesized that PCAF acts as multifactorial regulator of arteriogenesis. APPROACH AND RESULTS: After induction of hindlimb ischemia, blood flow recovery was impaired in both PCAF(-/-) mice and healthy wild-type mice treated with the pharmacological PCAF inhibitor Garcinol, demonstrating an important role for PCAF in arteriogenesis. PCAF deficiency reduced the in vitro inflammatory response in leukocytes and vascular cells involved in arteriogenesis. In vivo gene expression profiling revealed that PCAF deficiency results in differential expression of 3505 genes during arteriogenesis and, more specifically, in impaired induction of multiple proinflammatory genes. Additionally, recruitment from the bone marrow of inflammatory cells, in particular proinflammatory Ly6C(hi) monocytes, was severely impaired in PCAF(-/-) mice. CONCLUSIONS: These findings indicate that PCAF acts as master switch in the inflammatory processes required for effective arteriogenesis.


Asunto(s)
Arteritis/fisiopatología , Isquemia/fisiopatología , Neovascularización Fisiológica/inmunología , Factores de Transcripción p300-CBP/genética , Factores de Transcripción p300-CBP/inmunología , Acetilación , Animales , Arteritis/inmunología , Arteritis/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/inmunología , Miembro Posterior/irrigación sanguínea , Histonas/metabolismo , Isquemia/inmunología , Isquemia/metabolismo , Ratones , Ratones Noqueados , Monocitos/inmunología , Monocitos/patología , Linfocitos T/inmunología , Linfocitos T/patología , Terpenos/farmacología , Transcriptoma , Factores de Transcripción p300-CBP/antagonistas & inhibidores
16.
J Neurosci ; 33(16): 6857-63, 2013 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-23595744

RESUMEN

Blood-brain barrier (BBB) dysfunction is a major hallmark of many neurological diseases, including multiple sclerosis (MS). Using a genomics approach, we defined a microRNA signature that is diminished at the BBB of MS patients. In particular, miR-125a-5p is a key regulator of brain endothelial tightness and immune cell efflux. Our findings suggest that repair of a disturbed BBB through microRNAs may represent a novel avenue for effective treatment of MS.


Asunto(s)
Barrera Hematoencefálica/fisiopatología , Encéfalo/patología , Células Endoteliales/fisiología , Inflamación/patología , MicroARNs/metabolismo , Esclerosis Múltiple/patología , Barrera Hematoencefálica/efectos de los fármacos , Línea Celular Transformada , Citocinas/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Vectores Genéticos/fisiología , Humanos , MicroARNs/genética , ARN Interferente Pequeño/farmacología , Migración Transendotelial y Transepitelial/efectos de los fármacos , Transfección
17.
Eur Heart J ; 33(9): 1076-84, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-21831908

RESUMEN

AIMS: In patients with obstructive coronary artery disease (CAD), the growth of collateral arteries, i.e. arteriogenesis, can preserve myocardial tissue perfusion and function. Monocytes modulate this process, supplying locally the necessary growth factors and degrading enzymes. Knowledge on factors involved in human arteriogenesis is scarce. Thus, the aim of the present study is to identify targets in monocytes that are critical for arteriogenesis in patients with CAD. METHODS AND RESULTS: A total of 50 patients with a chronic total coronary occlusion were dichotomized according to their collateral flow index. From each patient, RNA was isolated from unstimulated peripheral blood monocytes, monocytes stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, and from macrophages. Increased mRNA expression of galectin-2 was found in three out of four monocytic cell types of patients with a low capacity of the collateral circulation (P= 0.03 for unstimulated monocytes; P= 0.02 for LPS-stimulated monocytes; P= 0.20 for IL-4-stimulated monocytes; P= 0.02 for macrophages). Additionally, galectin-2 mRNA expression was significantly associated with the rs7291467 polymorphism in LGALS2 encoding galectin-2 in all four monocytic cell types. Patient with the rs7291467 CC genotype displayed highest galectin-2 expression, and also tended to have a lower arteriogenic response. To evaluate the effect of galectin-2 on arteriogenesis in vivo, we used a murine hindlimb model. Treatment with galectin-2 markedly impaired the perfusion restoration at Day 7. CONCLUSION: Collectively, these results identify galectin-2 as a novel inhibitor of arteriogenesis. Modulation of galectin-2 may constitute a new therapeutic strategy for the stimulation of arteriogenesis in patients with CAD.


Asunto(s)
Circulación Colateral/genética , Oclusión Coronaria/genética , Galectina 2/metabolismo , Polimorfismo Genético/genética , Anciano , Animales , Fármacos Cardiovasculares/farmacología , Circulación Colateral/efectos de los fármacos , Oclusión Coronaria/metabolismo , Oclusión Coronaria/fisiopatología , Femenino , Galectina 2/genética , Galectina 2/farmacología , Miembro Posterior , Humanos , Interleucina-4/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Monocitos/efectos de los fármacos , ARN Mensajero/metabolismo
18.
Ann Rheum Dis ; 70(6): 1153-9, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21444302

RESUMEN

OBJECTIVE: Despite the fact that rituximab depletes B cells in all treated patients with RA, not all patients show a favourable clinical response. The goal of this study was to provide insight into pharmacological changes in peripheral blood that are associated with clinical response to rituximab. METHODS: Gene expression profiling was performed on peripheral blood RNA of 13 patients with RA (test group) using Illumina HumanHT beadchip microarrays. An independent group of nine patients was used for validation using TaqMan quantitative PCR. Clinical responder status was determined after 6 months using change in 28-joint Disease Activity Score (ΔDAS28) and European League Against Rheumatism (EULAR) response criteria. Significance analysis of microarrays and ontology analysis were used for data analysis and interpretation. RESULTS: Pharmacogenomic analyses demonstrated marked interindividual differences in the pharmacological responses at 3 and 6 months after start of treatment with rituximab. Interestingly, only differences in the regulation of type I interferon (IFN)-response genes after 3 months correlated with the ΔDAS28 response. Good responders (DAS>1.2; n=7) exhibited a selective increase in the expression of type I IFN-response genes, whereas this activity was unchanged or hardly changed in non-responders (DAS<1.2; n=6) (p=0.0040 at a cut-off of 1.1-fold induction). Similar results were obtained using EULAR response criteria. These results were validated in an independent cohort of nine patients (five non-responders and four responders, p=0.0317). CONCLUSIONS: A good clinical response to rituximab in RA is associated with a selective drug-induced increase in type I IFN-response activity in patients with RA. This finding may provide insight in the biological mechanism underlying the therapeutic response to rituximab.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Interferón Tipo I/biosíntesis , Adulto , Anciano , Artritis Reumatoide/inmunología , Biomarcadores/sangre , Análisis por Conglomerados , Femenino , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interferón Tipo I/sangre , Interferón Tipo I/genética , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Pronóstico , Rituximab , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
19.
BMC Genomics ; 11: 388, 2010 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-20565948

RESUMEN

BACKGROUND: Circulating CD34+ progenitor cells have the potential to differentiate into a variety of cells, including endothelial cells. Knowledge is still scarce about the transcriptional programs used by CD34+ cells from peripheral blood, and how these are affected in coronary artery disease (CAD) patients. RESULTS: We performed a whole genome transcriptome analysis of CD34+ cells, CD4+ T cells, CD14+ monocytes, and macrophages from 12 patients with CAD and 11 matched controls. CD34+ cells, compared to other mononuclear cells from the same individuals, showed high levels of KRAB box transcription factors, known to be involved in gene silencing. This correlated with high expression levels in CD34+ cells for the progenitor markers HOXA5 and HOXA9, which are known to control expression of KRAB factor genes. The comparison of expression profiles of CD34+ cells from CAD patients and controls revealed a less naïve phenotype in patients' CD34+ cells, with increased expression of genes from the Mitogen Activated Kinase network and a lowered expression of a panel of histone genes, reaching levels comparable to that in more differentiated circulating cells. Furthermore, we observed a reduced expression of several genes involved in CXCR4-signaling and migration to SDF1/CXCL12. CONCLUSIONS: The altered gene expression profile of CD34+ cells in CAD patients was related to activation/differentiation by a retinoic acid-induced differentiation program. These results suggest that circulating CD34+ cells in CAD patients are programmed by retinoic acid, leading to a reduced capacity to migrate to ischemic tissues.


Asunto(s)
Antígenos CD34/metabolismo , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/patología , Perfilación de la Expresión Génica , Células Madre/metabolismo , Tretinoina/metabolismo , Estudios de Casos y Controles , Diferenciación Celular/genética , Movimiento Celular/genética , Enfermedad de la Arteria Coronaria/sangre , Genómica , Humanos , Fenotipo
20.
Arthritis Rheum ; 62(3): 694-704, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20131234

RESUMEN

OBJECTIVE: To identify molecular features associated with the development of rheumatoid arthritis (RA), to understand the pathophysiology of preclinical development of RA, and to assign predictive biomarkers. METHODS: The study group comprised 109 anti-citrullinated protein antibody (ACPA)- and/or rheumatoid factor-positive patients with arthralgia who did not have arthritis but were at risk of RA, and 25 patients with RA. The gene expression profiles of blood samples obtained from these patients were determined by DNA microarray analysis and quantitative polymerase chain reaction. RESULTS: In 20 of the 109 patients with arthralgia who were at risk of RA, arthritis developed after a median of 7 months. Gene expression profiling of blood cells revealed heterogeneity among the at-risk patients, based on differential expression of immune-related genes. This report is the first to describe gene signatures relevant to the development of arthritis. Signatures significantly associated with arthritis development were involved in interferon (IFN)-mediated immunity, hematopoiesis, and chemokine/cytokine activity. Logistic regression analysis revealed that the odds ratio (OR) for developing arthritis within 12 months was 21.0 (95% confidence interval [95% CI] 2.8-156.1 [P = 0.003]) for the subgroup characterized by increased expression of genes involved in IFN-mediated immunity and/or cytokine/chemokine-activity. Genes involved in B cell immunology were associated with protection against progression to arthritis (OR 0.38, 95% CI 0.21-0.70 [P = 0.002]). These processes were reminiscent of those in patients with RA, implying that the preclinical phase of disease is associated with features of established disease. CONCLUSION: The results of this study indicate that IFN-mediated immunity, hematopoiesis, and cell trafficking specify processes relevant to the progression of arthritis independent of ACPA positivity. These findings strongly suggest that certain gene signatures have value for predicting the progression to arthritis, which will pave the way to preventive medicine.


Asunto(s)
Artralgia/genética , Artritis Reumatoide/genética , Autoanticuerpos/sangre , Expresión Génica , Artralgia/complicaciones , Artralgia/inmunología , Artritis Reumatoide/inmunología , Linfocitos B/inmunología , Femenino , Hematopoyesis/fisiología , Humanos , Interferones/fisiología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Factor Reumatoide/sangre
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