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AIMS: Inflammation plays a role in the development and progression of type 2 diabetes macroangiopathy. Interleukin 33 (IL-33) drives production of Th2-associated cytokines. The soluble form of suppression of tumorigenicity 2 (sST2) acting as a decoy receptor blocks IL-33 and tones down Th2 inflammatory response. We investigated the role of sST2 as a predictor of CV and all-cause mortality in a cohort of patients affected by established atherosclerotic disease. METHODS: 399 patients with atherosclerotic disease from the Tor Vergata Atherosclerosis Registry performed follow-up every year by phone interview. The primary endpoint was cardiovascular death and the secondary endpoint was death for any other disease. RESULTS: sST2 plasma levels were significantly increased from normal glucose-tolerant patients to patients with history of type 2 diabetes (p < 0.00001). Levels of sST2 were significantly correlated with fasting plasma glucose (R = 0.16, p = 0.002), HbA1c (R = 0.17, p = 0.002), and HOMA (R = 0.16, p = 0.004). Dividing patients in tertiles of sST2 levels, those belonging to the highest tertile showed an increased rate of all-cause and cardiovascular mortality, (all-cause mortality p = 0.045 and CVD mortality p = 0.02). A multivariate Cox analysis revealed that sST2 increased the risk in cardiovascular mortality per SD by hazard ratio 1.050 (95% CI 1.006-1.097, p = 0.025) after adjustment for age and hs-CRP while it did not significantly change the risk for all-cause mortality. CONCLUSIONS: High circulating level of sST2 is associated to increased CVD mortality and markers of metabolic dysfunction in subjects with atherosclerotic disease.
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Biomarcadores/sangre , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/mortalidad , Angiopatías Diabéticas/diagnóstico , Angiopatías Diabéticas/mortalidad , Trastornos del Metabolismo de la Glucosa/diagnóstico , Proteína 1 Similar al Receptor de Interleucina-1/sangre , Anciano , Anciano de 80 o más Años , Aterosclerosis/sangre , Aterosclerosis/diagnóstico , Aterosclerosis/etiología , Aterosclerosis/mortalidad , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Enfermedades Cardiovasculares/sangre , Causas de Muerte , Estudios de Cohortes , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidad , Angiopatías Diabéticas/sangre , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Trastornos del Metabolismo de la Glucosa/sangre , Trastornos del Metabolismo de la Glucosa/etiología , Trastornos del Metabolismo de la Glucosa/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Factores de RiesgoRESUMEN
In the version of this article originally published, the received date was missing. It should have been listed as 2 January 2018. The error has been corrected in the HTML and PDF versions of this article.
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BACKGROUND AND AIMS: We aimed to identify novel biomarkers for cardiovascular mortality through a non-targeted metabolomics approach in patients with established atherosclerotic disease from the Tor Vergata Atherosclerosis Registry (TVAR). METHODS: We compared the serum baseline metabolome of 19 patients with atherosclerosis suffering from cardiovascular death during follow-up with the baseline serum metabolome of 20 control patients matched for age, gender, body mass index (BMI) and atherosclerotic disease status, who survived during the observation period. RESULTS: Three metabolites were significantly different in the cardiovascular mortality (CVM) group compared to controls: 2-hydroxycaproate, gluconate and sorbitol. 2-hydroxycaproate (otherwise known as alpha hydroxy caproate) was also significantly correlated with time to death. The metabolites performed better when combined together rather than singularly on the identification of CVM status. CONCLUSIONS: Our analysis led to identify few metabolites potentially amenable of translation into the clinical practice as biomarkers for specific metabolic changes in the cardiovascular system in patients with established atherosclerotic disease.
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Aterosclerosis/sangre , Aterosclerosis/mortalidad , Caproatos/sangre , Hidroxiácidos/sangre , Anciano , Anciano de 80 o más Años , Aterosclerosis/diagnóstico , Biomarcadores/sangre , Estudios de Casos y Controles , Causas de Muerte , Femenino , Humanos , Italia/epidemiología , Masculino , Metabolómica/métodos , Valor Predictivo de las Pruebas , Pronóstico , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Factores de TiempoRESUMEN
Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.
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Diabetes Mellitus/genética , Metagenómica , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad/genética , Animales , Células Cultivadas , Estudios de Cohortes , Factores de Confusión Epidemiológicos , Trasplante de Microbiota Fecal , Femenino , Hepatocitos/metabolismo , Humanos , Metaboloma , Metabolómica , Ratones , Microbiota , Fenotipo , Transcriptoma/genéticaRESUMEN
AIM: Insulin resistance and type 2 diabetes are independent risk factors for cardiovascular diseases. Levels of C-peptide are increased in these patients and its role in the atherosclerosis progression was studied in vitro and in vivo over the past years. To evaluate the possible use of C-peptide as cardiovascular biomarkers, we designed an observational study in which we enrolled patients with mono- or poly-vascular atherosclerotic disease. METHODS: We recruited 431 patients with stable atherosclerosis and performed a yearly follow-up to estimate the cardiovascular and total mortality and cardiovascular events. RESULTS: We performed a mean follow-up of 56 months on 268 patients. A multivariate Cox analysis showed that C-peptide significantly increased the risk of cardiovascular mortality [Hazard Ratio: 1.29 (95% confidence interval: 1.02-1.65, p < 0.03513)] after adjustment for age, sex, diabetes treatment, estimated glomerular filtration rate and known diabetes status. Furthermore, levels of C-peptide were significantly correlated with metabolic parameters and atherogenic factors. CONCLUSION: C-peptide was associated with cardiovascular mortality independently of known diabetes status in a cohort of patients with chronic atherosclerotic disease. Future studies using C-peptide into a reclassification approach might be undertaken to consider its potential as a cardiovascular disease biomarker.
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Aterosclerosis/sangre , Aterosclerosis/mortalidad , Péptido C/sangre , Anciano , Aterosclerosis/diagnóstico , Biomarcadores/sangre , Causas de Muerte , Enfermedad Crónica , Diabetes Mellitus/sangre , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/mortalidad , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Sistema de Registros , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND AND AIMS: The O subfamily of forkhead (FoxO) 1 is a pivotal element in the regulation of endothelial activation. Compartmentalization and activity of FoxO1 is regulated by post translational modifications, but the implication in endothelial dysfunction and atherosclerosis remain controversial. Our aim was to identify FoxO1 related metabolic signatures in endothelial cells. METHODS AND RESULTS: Using metabolomics in human umbilical endothelial cells (HUVECs) overexpressing the wild type FoxO1 (FoxO1-WT), the acetylation defective mutant (FoxO1-KR), the unphosphorylated nuclear localized mutant (FoxO1-ADA) and the Green Fluorescent Protein (GFP) control vector, we identify metabolic pathways differentially affected by the different FoxO1 localization and activity. Among metabolites, asymmetric dimethylarginine (ADMA) was increased in FoxO1-ADA compared with FoxO1-WT and FoxO1-KR infected cells (p < 0.01). ADMA was further investigated to identify the molecular mechanisms to explain its link to FoxO1. We found that unrestrained FoxO1 activity leads to increase of ADMA via downregulation of its degrading enzyme, dimethylaminohydrolase (DDAH) 1. In human subjects (n = 89) the FoxO1/DDAH1/ADMA pathway marks unstable atherosclerosis. CONCLUSIONS: Our results point to ADMA as a biomarker to track deregulated FoxO1 activity in vivo.
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Amidohidrolasas/metabolismo , Arginina/análogos & derivados , Enfermedades de las Arterias Carótidas/enzimología , Factores de Transcripción Forkhead/metabolismo , Células Endoteliales de la Vena Umbilical Humana/enzimología , Arginina/metabolismo , Enfermedades de las Arterias Carótidas/genética , Células Cultivadas , Cromatografía Liquida , Regulación hacia Abajo , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Cromatografía de Gases y Espectrometría de Masas , Regulación Enzimológica de la Expresión Génica , Humanos , Metabolómica/métodos , Mutación , Transducción de Señal , TransfecciónRESUMEN
OBJECTIVE: In humans, it is unclear if insulin resistance at the monocyte level is associated with atherosclerosis in vivo. Here we have studied first-degree relatives of patients with type 2 diabetes to investigate whether a reduction in components of the insulin signal transduction pathways, such as the insulin receptor (InsR) or InsR substrate 1 or 2 (IRS1 or IRS2), or a reduction in genetic modifiers of insulin action, such as the TIMP3/ADAM17 (tissue inhibitor of metalloproteinase 3/A disintegrin and metalloprotease domain 17) pathway, is associated with evidence of atherosclerosis. RESEARCH DESIGN AND METHODS: Insulin sensitivity was analyzed through euglycemic-hyperinsulinemic clamp, and subclinical atherosclerosis was analyzed through intimal medial thickness. Monocytes were isolated through magnetic cell sorting, and mRNA and proteins were extracted and analyzed by quantitative PCR and pathscan enzyme-linked immunosorbent assays, respectively. RESULTS: In monocyte cells from human subjects with increased risk for diabetes and atherosclerosis, we found that gene expression, protein levels, and tyrosine phosphorylation of IRS2, but not InsR or IRS1, were decreased. TIMP3 was also reduced, along with insulin resistance, resulting in increased ectodomain shedding activity of the metalloprotease ADAM17. CONCLUSIONS: Systemic insulin resistance and subclinical atherosclerosis are associated with decreased IRS2 and TIMP3 expression in circulating monocytes.
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Diabetes Mellitus Tipo 2 , Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina/fisiología , Monocitos/metabolismo , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Adulto , Aterosclerosis/metabolismo , Grosor Intima-Media Carotídeo , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Resistencia a la Insulina/genética , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Inhibidor Tisular de Metaloproteinasa-3/genéticaRESUMEN
OBJECTIVE: To investigate the effect of pioglitazone on endothelial and adipose tissue dysfunction in newly detected IGT patients with CAD. METHODS AND DESIGN: Participants (n=25) were randomized to treatment with either placebo or pioglitazone (30 mg/day) for 12 weeks. Before and after treatment we evaluated endothelial function (flow-mediated dilation--FMD--of the brachial artery), circulating adipose and inflammatory markers (adiponectin isoforms, TNF-alpha, and high sensitivity-CRP), and insulin sensitivity (euglycemic hyperinsulinemic clamp). RESULTS: No significant changes were observed in subjects (n=12) treated with placebo. By contrast, subjects (n=13) treated with pioglitazone had significant improvement in FMD (10.8±5.3 vs 13.3±3.6%, p<0.01), accompanied by increased high molecular weight adiponectin (HMW-Ad) (1.7±1.2 vs 4.8±3.6 µg/ml, p<0.05) and decreased TNF-alpha (4.3±1.9 vs 3.2±1.2 pg/ml, p<0.05) associated to an increased glucose disposal (4.8±1.9 vs 5.4±2.0 mg kg(-1) min(-1), p<0.05). A multiple regression analysis indicated that increasing of HMW-Ad after pioglitazone predicted increased FMD. CONCLUSION: Pioglitazone significantly improves endothelial and adipose tissue dysfunction in pre-diabetic patients with CAD.
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Tejido Adiposo/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Estado Prediabético/tratamiento farmacológico , Tiazolidinedionas/uso terapéutico , Adiponectina/metabolismo , Tejido Adiposo/fisiopatología , Endotelio Vascular/fisiopatología , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , PioglitazonaRESUMEN
BACKGROUND & AIMS: Interleukin (IL)-21, a T-cell-derived cytokine, is overproduced in inflammatory bowel diseases (IBD), but its role in the pathogenesis of gut inflammation remains unknown. We here examined whether IL-21 is necessary for the initiation and progress of experimental colitis and whether it regulates specific pathways of inflammation. METHODS: Both dextran sulfate sodium colitis and trinitrobenzene sulfonic acid-relapsing colitis were induced in wild-type and IL-21-deficient mice. CD4(+)CD25(-) T cells from wild-type and IL-21-deficient mice were differentiated in T helper cell (Th)17-polarizing conditions, with or without IL-21 or an antagonistic IL-21R/Fc. We also examined whether blockade of IL-21 by anti-IL-21 antibody reduced IL-17 in cultures of IBD lamina propria CD3(+) T lymphocytes. Cytokines were evaluated by real-time polymerase chain reaction and/or enzyme-linked immunosorbent assay. RESULTS: High IL-21 was seen in wild-type mice with dextran sulfate sodium- and trinitrobenzene sulfonic acid-relapsing colitis. IL-21-deficient mice were largely protected against both colitides and were unable to up-regulate Th17-associated molecules during gut inflammation, thus suggesting a role for IL-21 in controlling Th17 cell responses. Indeed, naïve T cells from IL-21-deficient mice failed to differentiate into Th17 cells. Treatment of developing Th17 cells from wild-type mice with IL-21R/Fc reduced IL-17 production. Moreover, in the presence of transforming growth factor-beta1, exogenous IL-21 substituted for IL-6 in driving IL-17 induction. Neutralization of IL-21 reduced IL-17 secretion by IBD lamina propria lymphocytes. CONCLUSIONS: These results indicate that IL-21 is a critical regulator of inflammation and Th17 cell responses in the gut.