RESUMEN
AIMS: We examined associations of ferritin and 25-hydroxyvitamin D with fasting glucose and prevalent diabetes in older men. METHODS: Cross-sectional analysis of 4153 community-dwelling men aged 70 to 89 years in Western Australia. Plasma ferritin, 25-hydroxyvitamin D, and glucose were assayed. Diabetes was ascertained from self-report, medications, and fasting glucose. RESULTS: There were 577 men with diabetes (13.9%). In the whole cohort, ferritin was associated with fasting glucose (0.051 mmol/L per 1 SD increase in ferritin, P = .006) and 25-hydroxyvitamin D was inversely associated (-0.085 mmol/L per 1 SD, P < .001). Ferritin was not associated with prevalent diabetes (highest vs. lowest quartile; >225 vs <66 µg/L: adjusted odds ratio [OR] 0.97, 95% confidence interval [CI], 0.74-1.27, P = .83). Higher vitamin D was associated with decreased odds of prevalent diabetes (highest vs lowest quartile; >82 nmol/L vs <53 nmol/L: OR = 0.57, 95% CI = 0.43-0.75, P < .001). There was no interaction between ferritin and vitamin D on diabetes risk. CONCLUSIONS: In older men, ferritin is associated with fasting glucose but not prevalent diabetes. Higher 25-hydroxyvitamin D concentrations are independently associated with lower fasting glucose and reduced risk of diabetes. Clinical trials are required to determine whether interventions, which raise vitamin D concentrations, would reduce incidence of diabetes in this expanding demographic group.
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Biomarcadores/sangre , Diabetes Mellitus/sangre , Diabetes Mellitus/epidemiología , Ferritinas/sangre , Deficiencia de Vitamina D/fisiopatología , Vitamina D/análogos & derivados , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Glucemia/análisis , Estudios de Cohortes , Estudios Transversales , Ayuno , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Vida Independiente , Masculino , Pronóstico , Factores de Riesgo , Vitamina D/sangre , VitaminasRESUMEN
Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Thrombospondin-1 (TSP-1; gene Thbs1) is a member of the matricellular protein family important in the control of extracellular matrix (ECM) remodelling. In the present study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeated ultrasound for a median 5.5 years. AAA growth was negatively correlated with serum TSP-1 concentration (Spearman's rho -0.129, P=0.033). Men with TSP-1 in the highest quartile had a reduced likelihood of AAA growth greater than median during follow-up (OR: 0.40; 95% confidence interval (CI): 0.19-0.84, P=0.016, adjusted for other risk factors). Immunohistochemical staining for TSP-1 was reduced in AAA body tissues compared with the relatively normal AAA neck. To further assess the role of TSP-1 in AAA initiation and progression, combined TSP-1 and apolipoprotein deficient (Thbs1-/-ApoE-/-, n=20) and control mice (ApoE-/-, n=20) were infused subcutaneously with angiotensin II (AngII) for 28 days. Following AngII infusion, Thbs1-/- ApoE-/- mice had larger AAAs by ultrasound (P=0.024) and ex vivo morphometry measurement (P=0.006). The Thbs1-/-ApoE-/- mice also showed increased elastin filament degradation along with elevated systemic levels and aortic expression of matrix metalloproteinase (MMP)-9. Suprarenal aortic segments and vascular smooth muscle cells (VSMCs) isolated from Thbs1-/-ApoE-/- mice showed reduced collagen 3A1 gene expression. Furthermore, Thbs1-/-ApoE-/- mice had reduced aortic expression of low-density lipoprotein (LDL) receptor-related protein 1. Collectively, findings from the present study suggest that TSP-1 deficiency promotes maladaptive remodelling of the ECM leading to accelerated AAA progression.
Asunto(s)
Angiotensina II , Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/metabolismo , Trombospondina 1/sangre , Trombospondina 1/deficiencia , Animales , Aorta Abdominal/diagnóstico por imagen , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/sangre , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/prevención & control , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Biomarcadores/sangre , Células Cultivadas , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Elastina/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Noqueados , Oportunidad Relativa , Fenotipo , Proteolisis , Receptores de LDL/genética , Receptores de LDL/metabolismo , Factores de Riesgo , Trombospondina 1/genética , Factores de Tiempo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ultrasonografía , Remodelación VascularRESUMEN
OBJECTIVE: Interaction of the activating sequence in thrombospondin-1 (TSP-1) with the conserved sequence (leucine-serine-lysine-leucine [LSKL]) in the latency-associated peptide region of latent transforming growth factor (TGF)-ß complex is important in regulating TGF-ß1 activity. We aimed to assess the effect of blocking peptide LSKL on the progression of pre-established abdominal aortic aneurysm in angiotensin II-infused apolipoprotein E-deficient (ApoE(-/-)) mice. APPROACH AND RESULTS: Abdominal aortic aneurysm was established in 3-month-old male ApoE(-/-) mice with subcutaneous infusion of angiotensin II for 28 days. After this, mice received LSKL peptide or control SLLK (serine-leucine-leucine-lysine) peptide (4 mg/kg) via daily intraperitoneal injection for an additional 2 weeks. Administration of LSKL peptide promoted larger suprarenal aortic diameter, as determined by ultrasound and morphometric analysis, and stimulated more severe atherosclerosis within the aortic arch. In addition, mice receiving LSKL peptide exhibited elevated circulating proinflammatory cytokine levels and greater inflammatory cells within the suprarenal aorta compared with controls. Mice receiving LSKL peptide showed low plasma TGF-ß1 activity and low levels of aortic tissue phosphorylated to total Smad2/3. Aortic gene expression of TGF-ß receptor 1 (TGFBRI) and receptor 2 (TGFBRII), but not TGF-ß1 and thrombospondin-1, were lower in mice receiving LSKL peptide than controls. LSKL peptide administration was associated with greater aortic elastin fragmentation and lower expression and activity of the TGF-ß1-target gene lysyl oxidase like 1 (LOXL1). CONCLUSIONS: Attenuation of thrombospondin-1-directed activation of TGF-ß1 promotes abdominal aortic aneurysm and atherosclerosis progression in the angiotensin II-infused ApoE(-/-) mouse model.
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Angiotensina II , Aorta/efectos de los fármacos , Aneurisma de la Aorta Abdominal/inducido químicamente , Apolipoproteínas E/deficiencia , Aterosclerosis/inducido químicamente , Péptidos/toxicidad , Trombospondina 1/antagonistas & inhibidores , Aminoácido Oxidorreductasas/metabolismo , Animales , Aorta/metabolismo , Aorta/patología , Aneurisma de la Aorta Abdominal/sangre , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/patología , Apolipoproteínas E/genética , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Citocinas/sangre , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Elastina/metabolismo , Mediadores de Inflamación/sangre , Inyecciones Intraperitoneales , Masculino , Ratones Noqueados , Péptidos/administración & dosificación , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Trombospondina 1/metabolismo , Factores de Tiempo , Factor de Crecimiento Transformador beta1/sangreRESUMEN
BACKGROUND AND PURPOSE: Studies in rodent models suggest that upregulating angiopoietin-1 (Angpt1) improves stroke outcomes. The aims of this study were to assess the association of plasma Angpt1 with stroke occurrence and outcome. METHODS: Plasma Angpt1 was measured in 336 patients who had experienced a recent stroke and 321 healthy controls with no stroke history. Patients with stroke (n=285) were reassessed at 3 months and plasma Angpt1 concentration on admission compared between those with severe and minor disability as assessed by the modified Rankin scale. In a separate cohort of 4032 community-acquired older men prospectively followed for a minimum of 6 years, the association of plasma Angpt1 with stroke incidence was examined. RESULTS: Median plasma Angpt1 was 3-fold lower in patients who had experienced a recent stroke (6.42, interquartile range, 4.26-9.53 compared with 17.36; interquartile range, 14.01-22.46 ng/mL; P<0.001) and remained associated with stroke after adjustment for other risk factors. Plasma Angpt1 concentrations on admission were lower in patients who had severe disability or died at 3 months (median, 5.52; interquartile range, 3.81-8.75 ng/mL for modified Rankin scale 3-6; n=91) compared with those with minor disability (median, 7.04; interquartile range, 4.75-9.92 ng/mL for modified Rankin scale 0-2; n=194), P=0.012, and remained negatively associated with severe disability or death after adjusting for other risk factors. Plasma Angpt1 was not predictive of stroke incidence in community-dwelling older men. CONCLUSIONS: Plasma Angpt1 concentrations are low after ischemic stroke particularly in patients with poor stroke outcomes at 3 months. Interventions effective at upregulating Angpt1 could potentially improve stroke outcomes.
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Angiopoyetina 1/sangre , Isquemia Encefálica/sangre , Isquemia Encefálica/mortalidad , Evaluación de la Discapacidad , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/mortalidad , Anciano , Biomarcadores/sangre , Isquemia Encefálica/clasificación , Estudios de Casos y Controles , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/clasificaciónRESUMEN
AAA (abdominal aortic aneurysm) is an important cause of sudden death in older adults, but there is no current effective drug therapy for this disease. The UCNs (urocortins1-3) and their receptors: CRFR (corticotrophin-releasing factor receptor)-1 and -2 have been implicated in various CVDs (cardiovascular diseases). We assessed the relative expression of UCN1-3 in AAA by qRT-PCR (quantitative reverse transcription-PCR) and ELISA, and examined in vitro how UCN2 affects human aortic VSMC (vascular smooth muscle cell) Akt phosphorylation, pro-inflammatory cytokine IL (interleukin)-6 secretion, proliferation, cell cycle and apoptosis. UCN2 and CRFR2 expression were significantly up-regulated in biopsies from the AAA body. AAA body biopsies released high amounts of UCN2 in vitro. Median plasma UCN2 concentrations were 2.20 ng/ml (interquartile range 1.14-4.55 ng/ml, n=67) in AAA patients and 1.11 ng/ml (interquartile range 0.76-2.55 ng/ml, n=67) in patients with non-aneurysmal PAD (peripheral artery disease) (P=0.001). Patients with UCN2 in the highest quartile had a 4.12-fold (95% confidence interval, 1.37-12.40) greater prevalence of AAA independent of other risk factors, P=0.012. In vitro, UCN2 significantly inhibited VSMC Akt phosphorylation and proliferation in a dose-dependent manner. UCN2 induced VSMC G1 cell-cycle arrest and increased IL-6 secretion over 24 h. The CRFR2 antagonist astressin-2B significantly abrogated the effects of UCN2 on VSMCs. In conclusion, UCN2 is significantly associated with AAA and inhibits VSMC proliferation by inducing a G1 cell cycle arrest suggesting a plausible regulatory role in AAA pathogenesis.
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Aneurisma de la Aorta Abdominal/fisiopatología , Hormona Liberadora de Corticotropina/fisiología , Músculo Liso Vascular/patología , Receptores de Hormona Liberadora de Corticotropina/fisiología , Urocortinas/fisiología , Proliferación Celular , Células Cultivadas , Hormona Liberadora de Corticotropina/sangre , Humanos , Interleucina-8/metabolismo , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Urocortinas/sangreRESUMEN
BACKGROUND: Cardiovascular diseases have been associated with depression in later life, and a potential mechanism is inhibition of angiogenesis. We designed this study to determine if depression is associated with higher serum concentration of endostatin, an endogenous angiogenesis inhibitor. METHODS: We performed a cross-sectional examination of a random sample of men aged 69-86 years. Those who scored 7 or higher on the 15-item Geriatric Depression Scale were deemed depressed. We determined the concentration of serum endostatin using a reproducible assay. Other measures included age, education, body mass index, smoking, history of depression, use of antidepressants, hypertension, diabetes, coronary heart disease and stroke, high sensitivity C-reactive protein, plasma homocysteine, triglycerides and cholesterol. We used logistic regression to investigate the association between endostatin and depression, and adjusted the analyses for confounding factors. RESULTS: Our sample included 1109 men. Sixty-three (5.7%) men were depressed. Their serum endostatin was higher than that of nondepressed participants (p = 0.021). Men in the highest decile of endostatin had greater adjusted odds of depression (odds ratio [OR] 1.78, 95% confidence interval [CI] 1.03-3.06). A doubling of endostatin doubled the odds of depression (OR 1.93, 95% CI 1.31-2.84). The probability of depression increased with the concentration of endostatin in a log-linear fashion up to a maximum of about 20%-25%. LIMITATIONS: The cross-sectional design limits the study's ability to ascribe causality to the association between high endostatin and depression. CONCLUSION: Serum endostatin is associated with depression in older men. It remains to be established whether correction of this imbalance is feasible and could decrease the prevalence of depression in later life.
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Trastorno Depresivo/fisiopatología , Endostatinas/sangre , Anciano , Anciano de 80 o más Años , Análisis Químico de la Sangre , Estudios Transversales , Trastorno Depresivo/tratamiento farmacológico , Humanos , Modelos Logísticos , Masculino , Oportunidad Relativa , Probabilidad , Escalas de Valoración PsiquiátricaRESUMEN
AIMS: A number of biomarkers have been associated with abdominal aortic aneurysm (AAA), but there has been no assessment of how such markers along with clinical risk factors can be used to stratify the risk of AAA presence and its progression. The aims of this study were to assess the diagnostic, prognostic, and risk stratification potential of plasma D-dimer for AAA presence and growth. METHODS AND RESULTS: We included 1260 subjects (337 with AAA) recruited from a population screening study and 132 (41 with AAA) from a referral clinic. A total of 299 of the population group were followed by repeat ultrasound imaging for a median of 5.5 years to monitor AAA growth. The diagnostic and prognostic potential of plasma D-dimer was assessed by multivariate regression (adjusting for other AAA risk factors), receiver operator characteristic, and classification and regression tree (CART) analyses. In both groups, the dominant risk factor for AAA was D-dimer; thus in the population group, cut-off values of > 400 and > 900 ng/mL had adjusted odds ratios of 12.1 (95% CI 7.1-20.5) and 24.7 (95% CI 13.7-44.6), respectively. In both groups, CART analyses confirmed the dominating role of plasma D-dimer in defining extreme risk-groups with AAA prevalence as disparate as 3 and 82%. Average yearly AAA growth was positively and significantly associated with D-dimer which was able to predict growth as disparate as 0.4 and 2.5 mm/year. CONCLUSION: This study suggests that plasma D-dimer can play a role in the diagnosis and prognosis of AAA.
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Aneurisma de la Aorta Abdominal/diagnóstico , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Humanos , Masculino , Pronóstico , Análisis de Regresión , Factores de RiesgoRESUMEN
The aim of this study was to examine aortic biopsies with a cytokine array to identify new cytokines associated with abdominal aortic aneurysm (AAA). We assessed the relative expression of 79 cytokines using antibody-based cytokine arrays in a total of 12 AAA and 12 control aortic biopsies. Based on these findings we validated the findings for one cytokine by examining a further 11 AAA and 11 atherothrombosis biopsies and serum from 1028 men, 315 of whom had an AAA. Three cytokines (interleukins 1B and 8, and Chemokine CC motif ligand 22 [CCL22]) were consistently up-regulated in AAA biopsies. Since CCL22 had not previously been associated with aortic dilatation, we confirmed the upregulation of this cytokine in further tissue biopsies and serum using enzyme-linked immunosorbent assay. Median serum concentrations of CCL22 were greater in men with AAA (0.69 ng/ml) than controls (0.56 ng/ml, P < 0.01). Serum CCL22 was independently associated with both small (OR 1.51, 95% CI 1.21-1.88) and large AAA (OR 1.33, 95% CI 1.08-1.62) after adjusting for other risk factors. The association between CCL22 and AAA was also confirmed using immunohistochemistry. The results presented in this study demonstrate a novel association between CCL22 and AAA as well as illustrate how a protein array can be used to identify novel markers of potential pathogenic and diagnostic significance for AAA.
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Aneurisma de la Aorta Abdominal/metabolismo , Quimiocina CCL22/metabolismo , Regulación de la Expresión Génica , Anciano , Secuencias de Aminoácidos , Aorta/patología , Biopsia , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática/métodos , Humanos , Inmunohistoquímica/métodos , Masculino , Modelos Biológicos , Placa Aterosclerótica/patología , Factores de RiesgoRESUMEN
BACKGROUND: To investigate the association between aortic calcification, concentrations of stem-cell-mobilizing cytokines and osteocalcin-positive mononuclear cells in a mouse model and patients with peripheral artery disease. METHODS AND RESULTS: We estimated the concentration of the stem-cell-mobilizing cytokines stromal cell-derived factor α (SDF-1α), granulocyte colony stimulating factor and stem cell factor in a mouse model of aortic calcification developed in osteoprotegerin-deficient (OPG(-/-)) mice, as well as in patient plasma samples. Calcification was estimated by a colorimetric assay of extracts of harvested mice aortas and by computed tomographic angiogram images in patients. The cytokine concentrations were assessed for association with the severity of calcification and the percentage of osteocalcin-positive mononuclear cells (OCN(+) MNC) using non-parametric analysis. The serum concentration of stromal SDF-1α and granulocyte-colony stimulating factor (G-CSF) were significantly greater in OPG(-/-) compared to control mice. The percentage of circulating OCN(+) MNC was correlated to the concentration of SDF-1α in OPG(-/-) mice. These cytokines also correlated with the severity of calcification in OPG(-/-) mice. Patients with more severe calcification had a higher plasma concentration of the cytokines than those with less marked aortic calcification. The concentrations also correlated with circulating OCN(+) MNC and aortic calcification volumes. CONCLUSIONS: The association between stem cell cytokines, OCN(+) MNC and calcification suggests a possible role of bone-derived osteoprogenitor cells in the pathogenesis of vascular calcification.
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Aorta/patología , Calcinosis/patología , Movimiento Celular , Citocinas/sangre , Osteoblastos/patología , Células Madre/citología , Animales , Calcinosis/etiología , Citocinas/fisiología , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Noqueados , Osteocalcina/análisis , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Statins have been suggested to reduce expansion of abdominal aortic aneurysms (AAAs) independent of lipid-lowering effects. METHODS: We assessed the association of statin treatment and serum low-density lipoprotein (LDL) concentrations with small AAA expansion. Six hundred fifty-two patients undergoing surveillance of small AAAs were entered into the study from 5 vascular centers. In a subset, fasting lipids (n = 451) and other biomarkers (n = 216) were measured. The AAA diameter was followed by ultrasound surveillance for a median of 5 years. RESULTS: Three hundred forty-nine (54%) of the patients were prescribed statins. Adjusting for other risk factors, statin prescription was not associated with AAA growth (odds ratio [OR] 1.23, 95% CI 0.86-1.76). Above-median AAA growth was positively associated with initial diameter (OR 1.78 per 4.35-mm-larger initial aortic diameter, 95% CI 1.49-2.14) and negatively associated with diabetes (OR 0.37, 95% CI 0.22-0.62). Above-median serum LDL concentration was not associated with AAA growth. Patients receiving statins had lower serum C-reactive protein concentrations but similar matrix metalloproteinase-9 and interleukin-6 concentrations to those not prescribed these medications. CONCLUSIONS: We found no association between statin prescription or LDL concentration with AAA expansion. The results do not support the findings of smaller studies and suggest that statins may have no benefit in reducing AAA progression.
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Aneurisma de la Aorta Abdominal/sangre , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lipoproteínas LDL/sangre , Anciano , Progresión de la Enfermedad , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVE: We have previously demonstrated high concentrations of the glycoprotein osteoprotegerin (OPG) in biopsies of abdominal aortic aneurysm (AAA), and demonstrated that ligation of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) downregulates OPG in vitro and within a mouse model. The aims of this study were to assess the associations between circulating concentrations of OPG, polymorphisms of the gene encoding PPARgamma (PPARG), AAA presence and growth. DESIGN, PATIENTS AND MEASUREMENTS: Two genetic polymorphisms in PPARG were assessed in 4227 men, 699 of whom had an AAA. For 631 men, who had AAAs, maximum aortic diameter was monitored by yearly ultrasound for a median of 5 years. Plasma OPG was measured in 838 men, 318 of whom had an AAA. RESULTS: Plasma concentrations of OPG were independently associated with AAA (adjusted odds ratio 1.38, 95% CI 1.10-1.72). The PPARG c.1347C > T polymorphism was associated with plasma concentrations of OPG (beta 0.12, P < 0.01). The PPARG c.34G > C polymorphism was weakly associated with AAA (adjusted odds ratio 1.28, 95% CI 1.01-1.61). PPARG c.1347C > T was associated with increased AAA growth (recessive model, P = 0.03). CONCLUSIONS: Circulating concentrations of osteoprotegerin are associated with abdominal aortic aneurysm and with one peroxisome proliferator-activated receptor gamma gene polymorphism. Peroxisome proliferator-activated receptor gamma gene polymorphisms are weakly associated with abdominal aortic aneurysm presence and growth. Confirmation of these findings is required in other cohorts.
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Aneurisma de la Aorta Abdominal/sangre , Aneurisma de la Aorta Abdominal/genética , Osteoprotegerina/sangre , PPAR gamma/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Alelos , Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Estudios de Cohortes , Progresión de la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Osteoprotegerina/metabolismo , Polimorfismo de Nucleótido Simple/fisiologíaRESUMEN
BACKGROUND: Obesity is associated with occlusive artery disease but is not considered a risk factor for abdominal aortic aneurysm (AAA). We investigated the association between anthropometric measures of obesity, serum adipokines, and AAA. METHODS AND RESULTS: As part of a population study, we screened 12,203 men 65 to 83 years of age for AAA using ultrasound; 875 had an AAA (> or = 30 mm). Cardiovascular risk factors and waist and hip circumference were recorded. Serum adipokines were measured in 952 men, 318 of whom had an AAA. Waist circumference (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06 to 1.22) and waist-to-hip ratio (OR, 1.22; 95% CI, 1.09 to 1.37) were independently associated with AAA after adjustment for other known risk factors. The association was stronger for AAA > or = 40 mm (waist-to-hip ratio: OR, 1.53; 95% CI, 1.26 to 1.85). Serum resistin concentration was strongly independently associated with AAA (OR, 1.53; 95% CI, 1.32 to 1.76) and aortic diameter (beta=0.19, P<0.0001). Serum adiponectin was associated with AAA > or = 30 mm (OR, 1.26; 95% CI, 1.07 to 1.50) but not AAA > or = 40 mm (OR, 1.03; 95% CI, 0.77 to 1.39). Serum leptin was not associated with AAA. CONCLUSIONS: Measures of obesity are independently associated with AAA. Serum resistin concentrations were more strongly associated with aortic diameter than adipokines that are more intimately associated with adiposity. Further studies are required to investigate the mechanisms linking resistin and AAA.
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Adipoquinas/sangre , Aneurisma de la Aorta Abdominal/sangre , Aneurisma de la Aorta Abdominal/epidemiología , Salud del Hombre , Obesidad/sangre , Obesidad/epidemiología , Adiponectina/sangre , Anciano , Anciano de 80 o más Años , Glucemia , Proteína C-Reactiva/metabolismo , Humanos , Leptina/sangre , Masculino , Resistina/sangre , Factores de RiesgoRESUMEN
INTRODUCTION: Thrombomodulin (TM) is an important anti-coagulant protein that is down-regulated on endothelial cells overlying atherosclerotic plaques. We investigated the effects of the peroxisome proliferator-activated receptor (PPAR) ligands, fenofibrate and rosiglitazone, on the expression of TM ex vivo by advanced carotid atheromas, and in vitro by endothelial cells. METHODS: Adjacent carotid atheroma biopsies were incubated in vehicle control or PPAR ligand in explant culture for 4 days. Human aortic endothelial cells were incubated with PPAR ligands in vitro. TM expression was measured by Western blotting and flow cytometry. TM activity was assessed by generation of activated protein C. RESULTS: The PPAR-alpha activator, fenofibrate, up-regulated total TM expression within carotid explants by 1.7-fold (P<0.001) with no effect on activity. Rosiglitazone treatment had no effect on protein levels but reduced activity by 73% of the control (P<0.05). We noted disparate effects of PPAR ligands in atheroma samples from different patients and postulated that the response of endothelial cells to medication was influenced by the atheromatous environment. Incubation of human aortic endothelial cells with fenofibrate alone led to a dose-dependent increase in TM expression (P<0.05), however, in the presence of oxidized LDL a dose-dependent reduction in TM expression was induced by fenofibrate (P<0.05). CONCLUSIONS: The ability of fenofibrate to increase endothelial cell and carotid atheroma TM protein expression suggests a potential therapeutic role for this medication. The response to PPAR ligands likely varies depending on the exact constituents of individual atherosclerotic plaques, such as the relative amount of oxidized LDL.
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Aterosclerosis/metabolismo , Estenosis Carotídea/metabolismo , Células Endoteliales/efectos de los fármacos , Fenofibrato/farmacología , Tiazolidinedionas/farmacología , Trombomodulina/metabolismo , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Aterosclerosis/patología , Western Blotting , Estenosis Carotídea/patología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células Endoteliales/metabolismo , Citometría de Flujo , Humanos , Ligandos , Lipoproteínas LDL/efectos de los fármacos , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/efectos de la radiación , Técnicas de Cultivo de Órganos , Rosiglitazona , Rayos Ultravioleta , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVES: In vitro and animal studies have implicated osteopontin (OPN) in the pathogenesis of aortic aneurysm. The relationship between serum concentration of OPN and variants of the OPN gene with human abdominal aortic aneurysm (AAA) was investigated. METHODS AND RESULTS: OPN genotypes were examined in 4227 subjects in which aortic diameter and clinical risk factors were measured. Serum OPN was measured by ELISA in two cohorts of 665 subjects. The concentration of serum OPN was independently associated with the presence of AAA. Odds ratios (and 95% confidence intervals) for upper compared with lower OPN tertiles in predicting presence of AAA were 2.23 (1.29 to 3.85, P=0.004) for the population cohort and 4.08 (1.67 to 10.00, P=0.002) for the referral cohort after adjusting for other risk factors. In 198 patients with complete follow-up of aortic diameter at 3 years, initial serum OPN predicted AAA growth after adjustment for other risk factors (standardized coefficient 0.24, P=0.001). The concentration of OPN in the aortic wall was greater in patients with small AAAs (30 to 50 mm) than those with aortic occlusive disease alone. There was no association between five single nucleotide polymorphisms or haplotypes of the OPN gene and aortic diameter or AAA expansion. CONCLUSIONS: Serum and tissue concentrations of OPN are associated with human AAA. We found no relationship between variation of the OPN gene and AAA. OPN may be a useful biomarker for AAA presence and growth.
Asunto(s)
Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/metabolismo , Predisposición Genética a la Enfermedad , Osteopontina/genética , Osteopontina/metabolismo , Polimorfismo Genético , Adulto , Anciano , Aneurisma de la Aorta Abdominal/patología , Biopsia con Aguja , Estudios de Casos y Controles , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Genotipo , Humanos , Inmunohistoquímica , Modelos Logísticos , Masculino , Cadenas de Markov , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estadísticas no ParamétricasRESUMEN
BACKGROUND AND PURPOSE: Severely stenotic, symptomatic carotid atheromas are associated with a high risk of stroke in the short term. Although carotid endarterectomy is effective in reducing this stroke risk, it is frequently not applied within the time window for significant benefit. We investigated the effect of peroxisome proliferator-activated receptor (PPAR) -alpha and -gamma ligands in acutely modifying tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in unstable carotid atheromas. METHODS: During a 3-year period, 64 patients who had experienced a transient ischemic attack or stroke with good recovery within 6 weeks before surgery and 12 asymptomatic patients with a >70% carotid stenosis were recruited. The expression of PPAR-alpha and -gamma was investigated in endarterectomy samples. The effects of the PPAR-alpha and -gamma ligands fenofibrate and rosiglitazone were investigated in cell culture experiments. Targeted biopsy specimens from endarterectomy samples (n=48) were incubated with medication for 4 days. TF and TFPI were assessed by immunohistochemistry, Western blot analysis, flow cytometry, and activity assays. RESULTS: PPAR-gamma1 but not -alpha was downregulated in atheromas removed from patients with recent symptoms and no evidence of diabetes. Fenofibrate but not rosiglitazone impaired the induction of TF in human endothelial cells and reduced resting levels of TF activity in vascular smooth muscle cells. Rosiglitazone but not fenofibrate increased TFPI secretion from human endothelial cells. Both fenofibrate (100+/-18.7% to 56.6+/-8.8%, P=0.005; 0.2664+/-0.0696 to 0.1771+/-0.0310, P=0.02) and rosiglitazone (100+/-22% to 88.3+/-20%, P=0.02; 0.3113+/-0.0729 to 0.2287+/-0.0415, P=0.04) reduced TF expression and activity, respectively, in atheroma biopsy specimens. A low expression of TFPI was found in atheroma biopsy specimens with little evidence of TFPI activity. CONCLUSIONS: This study suggests that both PPAR-alpha and -gamma ligands have beneficial effects in acutely reducing TF in unstable carotid atheromas.
Asunto(s)
Estenosis Carotídea/fisiopatología , Lipoproteínas/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Tromboplastina/metabolismo , Anciano , Anciano de 80 o más Años , Estenosis Carotídea/complicaciones , Femenino , Fenofibrato/farmacología , Humanos , Ataque Isquémico Transitorio/etiología , Ataque Isquémico Transitorio/fisiopatología , Ligandos , Lipoproteínas/efectos de los fármacos , Masculino , Persona de Mediana Edad , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Rosiglitazona , Transducción de Señal , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/fisiopatología , Tiazolidinedionas/farmacología , Tromboplastina/efectos de los fármacosRESUMEN
Adenylyltransferase is a bifunctional enzyme that controls the enzymatic activity of dodecameric glutamine synthetase in Escherichia coli by reversible adenylylation and deadenylylation. Previous studies showed that the two similar but chemically distinct reactions are carried out by separate domains within adenylyltransferase. The N-terminal domain carries the deadenylylation activity, and the C-terminal domain carries the adenylylation activity [Jaggi R, van Heeswijk WC, Westerhoff HV, Ollis DL & Vasudevan SG (1997) EMBO J16, 5562-5571]. In this study, we further map the domain junctions of adenylyltransferase on the basis of solubility and enzymatic analysis of truncation constructs, and show for the first time that adenylyltransferase has three domains: the two activity domains and a central, probably regulatory (R), domain connected by interdomain Q-linkers (N-Q1-R-Q2-C). The various constructs, which have the opposing domain and or central domain removed, all retain their activity in the absence of their respective nitrogen status indicator, i.e. PII or PII-UMP. A panel of mAbs to adenylyltransferase was used to demonstrate that the cellular nitrogen status indicators, PII and PII-UMP, probably bind in the central regulatory domain to stimulate the adenylylation and deadenylylation reactions, respectively. In the light of these results, intramolecular signaling within adenylyltransferase is discussed.
Asunto(s)
Dominio Catalítico , Glutamato-Amoníaco Ligasa/metabolismo , Complejos Multienzimáticos/química , Nucleotidiltransferasas/química , Secuencia de Aminoácidos , Mapeo Epitopo , Escherichia coli/enzimología , Datos de Secuencia Molecular , Nucleotidiltransferasas/metabolismo , Proteínas PII Reguladoras del Nitrógeno/metabolismoRESUMEN
AIM: Matrix metalloproteinases (MMPs), angiotensin II (AII) and its receptors are implicated in atherosclerotic plaque instability, however the roles of the two receptor subtypes, ATR1 and ATR2, in MMP regulation remain uncertain. In this study, we investigated the effect of ATR1 and ATR2 blockade on the expression and activity of MMP-2, MMP-3 and MMP-9, in human carotid atheroma. METHODS: Atheroma samples (n=36) were obtained from patients undergoing carotid endarterectomy. The effects of ATR1 (irbesartan), ATR2 (PD123319) and combined ATR1 and ATR2 blockade on the expression and activity of the MMPs and the expression of tissue inhibitors of metalloproteinases (TIMPs) were investigated in explant culture experiments. Paired atheroma samples were incubated with the intervention or media control for 4 days. Protein levels (MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, TIMP-4, ATR1 and ATR2) were determined by ELISA. Overall gelatinase activity and specific activation were measured by chromogenic activity assays and zymography, respectively. RESULTS: ATR1 blockade, but not ATR2 blockade significantly reduced TIMP-1, TIMP-2 and TIMP-4 expression in atheroma supernatant. Combined ATR1 and ATR2 blockade significantly reduced MMP-2, MMP-3 and MMP-9 expression. MMP-2 and MMP-9 relative activation, and overall MMP-9 catalytic capacity were significantly increased by ATR1 blockade. CONCLUSIONS: Our findings suggest that ATR1 blockade reduces TIMP expression and increases gelatinase activity in human carotid atheroma.
Asunto(s)
Angiotensina II/metabolismo , Enfermedades de las Arterias Carótidas/metabolismo , Gelatinasas/metabolismo , Regulación Enzimológica de la Expresión Génica , Placa Aterosclerótica/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/metabolismo , Anciano , Western Blotting , Enfermedades de las Arterias Carótidas/fisiopatología , Ensayo de Inmunoadsorción Enzimática , Humanos , Técnicas In Vitro , Masculino , Placa Aterosclerótica/fisiopatologíaRESUMEN
It is estimated that 5% of Australians over the age of 18 have diabetes, with the number of new cases increasing every year. Type 2 diabetes (T2D) also represents a significant disease burden in the Australian indigenous population, where prevalence is three times greater than that of non-indigenous Australians. Prevalence of T2D has been found to be higher in rural and remote indigenous Australian populations compared with urban indigenous Australian populations. Several studies have also found that body mass index and waist circumference are not appropriate for the prediction of T2D risk in indigenous Australians. Regional and remote areas of Australia are endemic for a variety of mosquito-borne flaviviruses. Studies that have investigated seroprevalence of flaviviruses in remote aboriginal communities have found high proportions of seroconversion. The family Flaviviridae comprises several genera of viruses with non-segmented single-stranded positive sense RNA genomes, and includes the flaviviruses and hepaciviruses. Hepatitis C virus (HCV) has been shown to be associated with insulin resistance and subsequent development of T2D. Flaviviruses and HCV possess conserved proteins and subgenomic RNA structures that may play similar roles in the development of insulin resistance. Although dietary and lifestyle factors are associated with increased risk of developing T2D, the impact of infectious diseases such as arboviruses has not been assessed. Flaviviruses circulating in indigenous Australian communities may play a significant role in inducing glucose intolerance and exacerbating T2D.
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Diabetes Mellitus Tipo 2/epidemiología , Infecciones por Flavivirus/epidemiología , Flavivirus/patogenicidad , Hepacivirus/patogenicidad , Hepatitis C/epidemiología , Nativos de Hawái y Otras Islas del Pacífico , Australia/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/virología , Dieta/etnología , Femenino , Flavivirus/genética , Infecciones por Flavivirus/complicaciones , Infecciones por Flavivirus/etnología , Infecciones por Flavivirus/virología , Hepacivirus/genética , Hepatitis C/complicaciones , Hepatitis C/etnología , Hepatitis C/virología , Humanos , Resistencia a la Insulina , Estilo de Vida/etnología , Masculino , Prevalencia , Factores de Riesgo , Población Rural , Población UrbanaRESUMEN
BACKGROUND AND AIMS: Experimental studies using a rodent model have suggested that iron overload may contribute to abdominal aortic aneurysm (AAA) pathogenesis. METHODS: We assessed the association of total body iron, as measured by plasma ferritin, with AAA diagnosis, size and growth in 4024 community-dwelling older men screened for AAA, using logistic regression and linear mixed effects models. RESULTS: Plasma ferritin concentrations were similar in men who did (n = 293) and did not (n = 3731) have an AAA (median [inter-quartile range] concentrations 115.4 [63.0-203.1] and 128.5 [66.1-229.1] ng/mL respectively, p = 0.124). There was no association between plasma ferritin concentration and AAA diagnosis in unadjusted logistic regression (odds ratio (OR) for a 1 standard deviation increase: 0.880 [95%CI: 0.764-1.015]; p = 0.078), or when adjusting for AAA risk factors and factors known to influence circulating ferritin (OR for a 1 standard deviation increase: 0.898 [95% CI: 0.778-1.035]; p = 0.138). Iron overload prevalence (plasma ferritin concentrations >200 ng/mL) was lower in men with an AAA (25.3%) than those without (30.8%; p = 0.048), but was not associated with AAA diagnosis after adjusting as above (OR: 0.781 [95% CI:0.589-1.035]; p = 0.086). The association of iron overload with AAA growth was investigated in 265 men with small AAAs who received at least 1 repeat ultrasound scan in the 3 years following screening. We saw no difference in AAA growth between men who did and did not have iron overload (n = 65 and 185 respectively, p = 0.164). CONCLUSIONS: Our data suggest that iron overload is unlikely to be important in AAA pathogenesis.
Asunto(s)
Aneurisma de la Aorta Abdominal/sangre , Aneurisma de la Aorta Abdominal/diagnóstico , Ferritinas/sangre , Hierro de la Dieta , Anciano , Biomarcadores/sangre , Estudios de Cohortes , Comorbilidad , Femenino , Humanos , Sobrecarga de Hierro , Modelos Lineales , Masculino , Prevalencia , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: A number of studies have suggested that angiotensin II (AII) receptor type 1 (ATR1) blocking drugs (ARBs) have anti-inflammatory effects however the mechanisms responsible are poorly investigated. OBJECTIVE: To determine the role of extracellular signal regulated kinase (ERK)1/2 in ARB induced anti-inflammatory effects within human carotid atherosclerosis. METHODS: Atheroma samples obtained from patients undergoing carotid endarterectomy were cultured with and without ATR1 (irbesartan), ERK1/2 (PD98059), AII ([Sar(1), Ile(8)]-AII) and angiotensin converting enzyme (ACE)2 (DX600) blockade. The in vitro effects of ATR1 and ERK1/2 blockade and exogenous AII on serum stimulated healthy, primary vascular cells were also investigated. Outcome was assessed by measuring cytokine, (interleukin (IL)-6, IL-8, C-C motif chemokine (CCL)2, C-X-C motif chemokine (CXCL)5, osteoprotegerin (OPG), osteopontin (OPN), CXCL16), concentrations in supernatants and phosphorylated ERK1/2 in the tissue lysates using ELISA. ERK1/2 expression in the tissue was assessed using Western blotting. RESULTS: Irbesartan reduced concentrations of IL-6, IL-8, CCL2, CXCL5, OPG, OPN and CXCL16 in both atheroma and primary vascular cell culture supernatants. The reduction in cytokine levels in the atheroma supernatant was correlated to a reduction in ERK1/2 expression in the tissue. Inhibition of ERK1/2 downregulated IL-6, IL-8 and CXCL5 in both atheroma and cell culture supernatants. AII and ACE2 blockade had no impact on cytokine or active ERK1/2 levels in the atheroma culture. CONCLUSION: Our findings suggest that ATR1 blockade downregulates atheroma tissue ERK1/2 expression leading to a reduction in cytokine production and that a non-AII agonist ATR1 signalling response may induce expression of these inflammation associated cytokines in the atheroma.