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BACKGROUND: Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is a major contributor to the development of atherosclerotic process. In a previous work, we demonstrated that the insulin receptor isoform A (IRA) and its association with the insulin-like growth factor-I receptor (IGF-IR) confer a proliferative advantage to VSMCs. However, the role of IR and IGF-IR in VSMC migration remains poorly understood. METHODS: Wound healing assays were performed in VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR-/- VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs). To study the role of IR isoforms and IGF-IR in experimental atherosclerosis, we used ApoE-/- mice at 8, 12, 18 and 24 weeks of age. Finally, we analyzed the mRNA expression of total IR, IRB isoform, IGF-IR and IGFs by qRT-PCR in the medial layer of human aortas. RESULTS: IGF-I strongly induced migration of the four cell lines through IGF-IR. In contrast, insulin and IGF-II only caused a significant increase of IRA VSMC migration which might be favored by the formation of IRA/IGF-IR receptors. Additionally, a specific IGF-IR inhibitor, picropodophyllin, completely abolished insulin- and IGF-II-induced migration in IRB, but not in IRA VSMCs. A significant increase of IRA and IGF-IR, and VSMC migration were observed in fibrous plaques from 24-week-old ApoE-/- mice. Finally, we observed a marked increase of IGF-IR, IGF-I and IGF-II in media from fatty streaks as compared with both healthy aortas and fibrolipidic lesions, favoring the ability of medial VSMCs to migrate into the intima. CONCLUSIONS: Our data suggest that overexpression of IGF-IR or IRA isoform, as homodimers or as part of IRA/IGF-IR hybrid receptors, confers a stronger migratory capability to VSMCs as might occur in early stages of atherosclerotic process.
Assuntos
Aterosclerose/metabolismo , Movimento Celular , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptor Cross-Talk , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Dieta Ocidental , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Insulina/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Fator de Crescimento Insulin-Like II/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Isoformas de Proteínas , Receptor Cross-Talk/efeitos dos fármacos , Receptor IGF Tipo 1/agonistas , Receptor IGF Tipo 1/genética , Receptor de Insulina/agonistas , Receptor de Insulina/genética , Receptores de Somatomedina/genética , Receptores de Somatomedina/metabolismo , Transdução de Sinais , Fatores de TempoRESUMO
OBJECTIVE: The study aimed to test the potential role of insulin-like growth factor I (IGF-I) and IGF-II as biomarkers for abdominal aortic aneurysm (AAA). METHODS AND RESULTS: IGF-I and II levels were analysed in 115 patients with screening diagnosed AAA kept under annual surveillance for 10 years. Serum IGF-I correlated positively with AAA size and growth rate (r = 0.23, P = 0.016 and r = 0.27, P = 0.004), persisting after adjustment for potential confounders. Serum IGF-I level predicted cases needing later surgery (AOC: 0.63; 95% confidence interval: 0.52-0.73). CONCLUSIONS: In this prospective, long-term study, baseline serum IGF-I correlated positively with AAA size and growth rate and predicted future need for preventive surgery.
Assuntos
Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/diagnóstico , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Vigilância da População , Aneurisma da Aorta Abdominal/terapia , Biomarcadores/sangue , Estudos de Coortes , Humanos , Valor Preditivo dos TestesRESUMO
INTRODUCTION: Type-2 diabetes mellitus (T2DM) is associated with early and severe atherosclerosis. However, few biomarkers can predict cardiovascular events in this population. METHODS: We followed 964 patients with coronary artery disease (CAD), assessing plasma levels of galectin-3, monocyte chemoattractant protein-1 (MCP-1), and N-terminal fragment of brain natriuretic peptide (NT-proBNP) at baseline. The secondary outcomes were acute ischemia and heart failure or death. The primary outcome was the combination of the secondary outcomes. RESULTS: Two hundred thirty-two patients had T2DM. Patients with T2DM showed higher MCP-1 (144 (113-195) vs. 133 (105-173) pg/mL, p = 0.006) and galectin-3 (8.3 (6.5-10.5) vs. 7.8 (5.9-9.8) ng/mL, p = 0.049) levels as compared to patients without diabetes. Median follow-up was 5.39 years (2.81-6.92). Galectin-3 levels were associated with increased risk of the primary outcome in T2DM patients (Hazard ratio (HR) 1.57 (1.07-2.30); p = 0.022), along with a history of cerebrovascular events. Treatment with clopidogrel was associated with lower risk. In contrast, NT-proBNP and MCP-1, but not galectin-3, were related to increased risk of the event in nondiabetic patients (HR 1.21 (1.04-1.42); p = 0.017 and HR 1.23 (1.05-1.44); p = 0.012, respectively), along with male sex and age. Galectin-3 was also the only biomarker associated with the development of acute ischemic events and heart failure or death in T2DM patients, while, in nondiabetics, MCP-1 and NT-proBNP, respectively, were related to these events. CONCLUSION: In CAD patients, galectin-3 plasma levels are associated with cardiovascular events in patients with T2DM, and MCP-1 and NT-proBNP in those without T2DM.
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INTRODUCTION: Serological biomarkers could reflect asymptomatic infrarenal aortic aneurysm (AAA) activity and guide patient management. REPORT: Serum concentrations of C-reactive protein (CRP), alpha 1-antitrypsin and lipoprotein(a) were measured in blood samples from 35 AAA patients and 35 controls and correlated with the aortic diameter and AAA growth in the previous 12 months. We found a positive correlation between CRP and AAA diameter (r=0.46; p=0.007) and alpha 1-antitrypsin and AAA growth (r=0.55; p=0.004). CONCLUSIONS: Alpha 1-antitrypsin may be a promising biomarker of AAA growth.
Assuntos
Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/patologia , Proteína C-Reativa/análise , Lipoproteína(a)/sangue , alfa 1-Antitripsina/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Projetos PilotoRESUMO
New biomarkers of cardiovascular disease are needed to augment the information obtained from traditional indicators and to illuminate disease mechanisms. One of the approaches used in metabolomics/metabonomics for that purpose is metabolic fingerprinting aiming to profile large numbers of chemically diverse metabolites in an essentially nonselective way. In this study, gas chromatography-mass spectrometry was employed to evaluate the major metabolic changes in low molecular weight plasma metabolites of patients with acute coronary syndrome (n = 9) and with stable atherosclerosis (n = 10) vs healthy subjects without significant differences in age and sex (n = 10). Reproducible differences between cases and controls were obtained with pattern recognition techniques, and metabolites accounting for higher weight in the classification have been identified through their mass spectra. On this basis, it seems inherently plausible that even a simple metabolite profile might be able to offer improved clinical diagnosis and prognosis, but in addition, specific markers are being identified.
Assuntos
Síndrome Coronariana Aguda/sangue , Cromatografia Gasosa-Espectrometria de Massas/métodos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Essentials Abdominal aortic aneurysm (AAA) is asymptomatic and its evolution unpredictable. To find novel potential biomarkers of AAA, microvesicles are an excellent source of biomarkers. Ficolin-3 is increased in microvesicles obtained from activated platelets and AAA tissue. Increased ficolin-3 plasma levels are associated with AAA presence and progression. SUMMARY: Background Abdominal aortic aneurysm (AAA) patients are usually asymptomatic and AAA evolution is unpredictable. Ficolin-3, mainly synthesized by the liver, is a molecule of the lectin complement-activation pathway involved in AAA pathophysiology. Objectives To define extra-hepatic sources of ficolin-3 in AAA and investigate the role of ficolin-3 as a biomarker of the presence and progression of AAA. Methods Microvesicles (exosomes and microparticles) were isolated from culture-conditioned medium of ADP-activated platelets, as well as from AAA tissue-conditioned medium (thrombus and wall). Ficolin-3 levels were analyzed by western-blot, real-time PCR, immunohistochemistry and ELISA. Results Increased ficolin-3 levels were observed in microvesicles isolated from activated platelets. Similarly, microvesicles released from AAA tissue display increased ficolin-3 levels as compared with those from healthy tissue. Moreover, ficolin-3 mRNA levels in the AAA wall were greatly increased compared with healthy aortic walls. Immunohistochemistry of AAA tissue demonstrated increased ficolin-3, whereas little staining was present in healthy walls. Finally, increased ficolin-3 levels were observed in AAA patients' plasma (n = 478) compared with control plasma (n = 176), which persisted after adjustment for risk factors (adjusted odds ratio [OR], 5.29; 95% confidence interval [CI], 3.27, 8.57)]. Moreover, a positive association of ficolin-3 with aortic diameter (Rho, 0.25) and need for surgical repair was observed, also after adjustment for potential confounding factors (adjusted hazard ratio, 1.55; 95% CI, 1.11, 2.15). Conclusions In addition to its hepatic expression, ficolin-3 may be released into the extracellular medium via microvesicles, by both activated cells and pathological AAA tissue. Ficolin-3 plasma levels are associated with the presence and progression of AAA, suggesting its potential role as a biomarker of AAA.
Assuntos
Aneurisma da Aorta Abdominal/sangue , Glicoproteínas/sangue , Lectinas/sangue , Idoso , Biomarcadores/sangue , Plaquetas/metabolismo , Meios de Cultivo Condicionados/química , Dinamarca , Progressão da Doença , Humanos , Hipertensão/diagnóstico , Masculino , Programas de Rastreamento , Microcirculação , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnósticoRESUMO
BACKGROUND: Apoptosis of vascular cells is considered to be a major determinant of atherosclerotic plaque vulnerability and potential rupture. Plasmin can be generated in atherosclerotic plaques and recent in vitro data suggest that plasminogen activation may trigger vascular smooth muscle cell (VSMC) apoptosis. AIM: To determine whether plasminogen activation may induce aortic VSMC apoptosis ex vivo and in vivo. METHODS AND RESULTS: Mice with single or combined deficiencies of apolipoprotein E (ApoE) and plasminogen activator inhibitor-1 (PAI-1) were used. Ex vivo incubation with plasminogen of isolated aortic tunica media from PAI-1-deficient mice induced plasminogen activation and VSMC apoptosis, which was inhibited by alpha2-antiplasmin. In vivo, levels of plasmin, active caspase 3 and VSMC apoptotic index were significantly higher in atherosclerotic aortas from mice with combined ApoE and PAI-1 deficiencies than in those from littermates with single ApoE deficiency. A parallel decrease in VSMC density was observed. CONCLUSIONS: These data strongly suggest that plasminogen activation may contribute to VSMC apoptosis in atherosclerotic plaques.
Assuntos
Aorta/metabolismo , Apoptose , Aterosclerose/metabolismo , Músculo Liso Vascular/metabolismo , Plasminogênio/metabolismo , Túnica Média/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Apolipoproteínas E/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Fibrinolisina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Inibidor 1 de Ativador de Plasminogênio/genética , Túnica Média/efeitos dos fármacos , Túnica Média/patologia , alfa 2-Antiplasmina/farmacologiaRESUMO
BACKGROUND: Abnormalities of mineral metabolism and inflammation may affect the cardiovascular system. We have assessed the relationship of left ventricular hypertrophy (LVH) with inflammation and mineral metabolism. METHODS: LVH was measured in 146 outpatients with stable coronary artery disease (SCAD) using echocardiography. Calcidiol (a vitamin D metabolite), parathyroid hormone (PTH), fibroblast growth factor-23, high-sensitivity C-reactive protein, MCP-1 (monocyte chemoattractant protein-1), galectin-3, NGAL (neutrophil gelatinase-associated lipocalin), and sTWEAK (soluble TNF-related weak inducer of apoptosis) plasma levels were studied. RESULTS: LVH, defined as septal thickness ≥11 mm, was present in 19.9% of cases. These patients were older [75.0 (61.0-81.0) vs 64.0 (51.0-76.0) years; p=0.002], had higher prevalence of left ventricular ejection fraction (LVEF)>40%, and had higher PTH [84.7 (59.6-104.7) vs 63.2 (49.2-85.2) pg/ml; p=0.007], galectin-3 [9.6 (8.0-11.1) vs 8.3 (6.9-9.9) ng/ml; p=0.037], and NGAL (208.5±87.6 vs 173.9±73.4 ng/ml; p=0.031) plasma levels than those without LVH. Glomerular filtration rate was lower in patients with LVH than in those without it (65.1±20.0 vs 74.7±19.9 mL/min/1.73 m2; p=0.021). There were no significant differences in hypertension (79.3 vs 68.4%; p=0.363) or sex between both groups. Variables showing differences based on univariate analysis and hypertension were entered into a logistic regression analysis. Only age [odds ratio (OR) =1.052 (1.011-1.096); p=0.013], PTH plasma levels [OR=1.017 (1.003-1.031); p=0.021], and LVEF>40% [OR=7.595 (1.463-39.429); p=0.016] were independent predictors of LVH. CONCLUSIONS: In patients with SCAD, elevated PTH levels are independently associated with the presence of LVH. Further studies are needed to elucidate the role of PTH in the development of myocardial hypertrophy.
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Doença da Artéria Coronariana/complicações , Hipertrofia Ventricular Esquerda/etiologia , Hormônio Paratireóideo/sangue , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Cardiovascular disease, including atherothrombosis, is the most frequent cause of mortality in the Western World. In the last years, major advances have been made in the pathogenesis of this disease. Currently, the drugs most widely used are the inhibitors of the HMG-CoA reductase (statins) and the antihypertensive drugs, mainly angiotensin II blockers. The first group has been shown to be effective on cardiovascular disease due to atherothrombosis, and the second group on hypertensive disease. Nevertheless, recent data suggest that these two situations can improve with the concomitant use of both drugs.
Assuntos
Angiotensina II/antagonistas & inibidores , Arteriosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anticolesterolemiantes/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Arteriosclerose/fisiopatologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Inibidores de Ciclo-Oxigenase/uso terapêutico , Endotélio Vascular/fisiopatologia , Haplorrinos , Humanos , Hipertensão/tratamento farmacológico , Metabolismo dos Lipídeos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
Iron deposits are observed in tissue of abdominal aortic aneurysm (AAA) patients, although the underlying mechanisms are not completely elucidated. Therefore we explored circulating markers of iron metabolism in AAA patients, and tested if they could serve as biomarkers of AAA. Increased red blood cell (RBC)-borne iron retention and transferrin, transferrin receptor and ferritin expression was observed in AAA tissue compared to control aorta (immunohistochemistry and western blot). In contrast, decreased circulating iron, transferrin, mean corpuscular haemoglobin concentration (MCHC) and haemoglobin concentration, along with circulating RBC count, were observed in AAA patients (aortic diameter >3 cm, n=114) compared to controls (aortic diameter <3 cm, n=88) (ELISA), whereas hepcidin concentrations were increased in AAA subjects (MS/MS assay). Moreover, iron, transferrin and haemoglobin levels were negatively, and hepcidin positively, correlated with aortic diameter in AAA patients. The association of low haemoglobin with AAA presence or aortic diameter was independent of specific risk factors. Moreover, MCHC negatively correlated with thrombus area in another cohort of AAA patients (aortic diameter 3-5 cm, n=357). We found that anaemia was significantly more prevalent in AAA patients (aortic diameter >5 cm, n=8,912) compared to those in patients with atherosclerotic aorto-iliac occlusive disease (n=17,737) [adjusted odds ratio=1.77 (95% confidence interval: 1.61;1.93)]. Finally, the mortality risk among AAA patients with anaemia was increased by almost 30% [adjusted hazard ratio: 1.29 (95% confidence interval: 1.16;1.44)] as compared to AAA subjects without anaemia. In conclusion, local iron retention and altered iron recycling associated to high hepcidin and low transferrin systemic concentrations could lead to reduced circulating haemoglobin levels in AAA patients. Low haemoglobin levels are independently associated to AAA presence and clinical outcome.
Assuntos
Anemia/diagnóstico , Aorta/metabolismo , Aneurisma da Aorta Abdominal/diagnóstico , Biomarcadores/metabolismo , Eritrócitos/fisiologia , Hemoglobinas/metabolismo , Ferro/metabolismo , Idoso , Anemia/complicações , Anemia/mortalidade , Aorta/patologia , Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/mortalidade , Feminino , Ferritinas/metabolismo , Hepcidinas/metabolismo , Humanos , Masculino , Prognóstico , Receptores da Transferrina/metabolismo , Fatores de Risco , Análise de Sobrevida , Transferrina/metabolismoRESUMO
High-density lipoproteins (HDLs) represent a family of particles characterized by the presence of apolipoprotein A-I (apoA-I) and by their ability to transport cholesterol from peripheral tissues back to the liver. In addition to this function, HDLs display pleiotropic effects including antioxidant, anti-apoptotic, anti-inflammatory, anti-thrombotic or anti-proteolytic properties that account for their protective action on endothelial cells. Vasodilatation via production of nitric oxide is also a hallmark of HDL action on endothelial cells. Endothelial cells express receptors for apoA-I and HDLs that mediate intracellular signalling and potentially participate in the internalization of these particles. In this review, we will detail the different effects of HDLs on the endothelium in normal and pathological conditions with a particular focus on the potential use of HDL therapy to restore endothelial function and integrity.
Assuntos
Endotélio Vascular/metabolismo , Lipoproteínas HDL/metabolismo , Modelos Biológicos , Receptores de Lipoproteínas/metabolismo , Vasculite/metabolismo , Animais , Apoptose , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Angiopatias Diabéticas/imunologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/terapia , Sistemas de Liberação de Medicamentos , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/uso terapêutico , Lisofosfolipídeos , Esfingosina/análogos & derivados , Vasculite/imunologia , Vasculite/fisiopatologia , Vasculite/terapiaRESUMO
OBJECTIVE: Cytokines are important mediators of immune-inflammatory responses implicated in abdominal aortic aneurysm (AAA) pathogenesis. Our objective was to investigate the cytokine expression profile in plasma of AAA patients. METHODS: Cytokine protein expression was measured in plasma of 5 large AAA patients (aortic size >50mm) and 5 controls (aortic size <30 mm) using a 20-cytokine antibody-based protein array. IGFBP-1 plasma concentrations were analyzed by ELISA. IGFBP-1 protein levels were analyzed in AAA thrombus by immunohistochemistry and Western blot. Platelet aggregation was assessed by conventional optical aggregometry. RESULTS: Several proteins including MIP-3 alpha (CCL20), Eotaxin-2 and IGFBP-1 were increased in AAA patients compared to controls. Among them, IGFBP-1 concentrations were significantly higher in large AAA patients vs control subjects. These data were validated in plasma of patients with large AAA (n = 30) compared to matched controls (n = 30) [834(469-1628) vs 497(204-893) pg/ml, p<0.01]. Furthermore, the potential association of IGFBP-1 with AAA size was analyzed in a second independent group of subjects [large AAA (n = 59), small AAA patients (aortic size = 30-50mm, n = 54) and controls (n = 30)]. Interestingly, IGFBP-1 levels correlated with AAA size (r = 0.4, p<0.001), which remained significant after adjusting for traditional risk factors. IGFBP-1 was localized in the luminal part of AAA thrombus and IGFBP-1 levels were increased in AAA thrombus conditioned media compared to media layer and healthy media. Interestingly, IGFBP-1 abrogated the potentiation of ADP-induced platelet aggregation triggered by IGF-1. CONCLUSIONS: IGFBP-1 has been identified by a protein array approach as a potential novel biomarker of AAA. The biological role of IGFBP-1 in AAA pathogenesis could be related to the modulation on the effect of IGF-1 on platelet aggregation.
Assuntos
Aneurisma da Aorta Abdominal/sangue , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Análise Serial de Proteínas , Proteômica/métodos , Idoso , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/imunologia , Aortografia/métodos , Biomarcadores/sangue , Western Blotting , Estudos de Casos e Controles , Meios de Cultivo Condicionados/metabolismo , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Fator de Crescimento Insulin-Like I/metabolismo , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Agregação Plaquetária , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Espanha , Técnicas de Cultura de Tecidos , Tomografia Computadorizada por Raios X , Regulação para CimaRESUMO
OBJECTIVES: Diminished soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) concentrations are associated with cardiovascular diseases. We have analyzed sTWEAK levels and its relation with expansion rate in subjects with abdominal aortic aneurysm (AAA). METHODS: sTWEAK levels were measured by ELISA. RESULTS: sTWEAK concentrations were diminished in small AAA (≤ 5 cm; 353 ± 12 pg/mL; n = 25, p = 0.03) and large AAA (>5 cm; 315 ± 21 pg/mL; n = 18, p = 0.004) compared with healthy subjects (411 ± 22 pg/mL; n=27). Moreover, sTWEAK concentrations were negatively associated with AAA size (r = -0.4; p = 0.008). sTWEAK was also negatively associated with AAA expansion rate with 5 years of follow-up (n = 79, r = -0.263; p = 0.031). Multivariate regression analysis revealed that sTWEAK levels were independently associated with AAA growth rate (ß = -0.208; p = 0.046). CONCLUSIONS: sTWEAK plasma levels were decreased in subjects with AAA and were independently related with AAA expansion rate indicating that this protein could be a novel diagnostic and prognostic biomarker of AAA.
Assuntos
Aneurisma da Aorta Abdominal/sangue , Fatores de Necrose Tumoral/sangue , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Biomarcadores/sangue , Estudos de Casos e Controles , Citocina TWEAK , Dinamarca , Progressão da Doença , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Modelos Logísticos , Prognóstico , Medição de Risco , Fatores de Risco , Espanha , Fatores de Tempo , UltrassonografiaRESUMO
OBJECTIVE: Oxidative stress is a main mechanism involved in vascular pathologies. Increased thioredoxin (TRX) levels have been observed in several oxidative stress-associated cardiovascular diseases. We aim to test the potential role of TRX as a biomarker of oxidative stress in abdominal aortic aneurysm (AAA). METHODS: TRX levels were analysed in both AAA intraluminal thrombus (ILT) tissue and in tissue-conditioned media by immunohistochemistry, Western blot and ELISA. Moreover, serum TRX levels were assessed in AAA Caucasian patients by ELISA. RESULTS: TRX was mainly localized in the luminal part of ILT in AAA. Compared with the abluminal layer, TRX release was increased in the luminal layer of the ILT of AAA (31+/-9 ng/ml vs. 9+/-3 ng/ml, p<0.05). The interest of this approach is that we can identify proteins potentially released into the blood compartment, which could serve as biomarkers of the pathology. In a training population, serum TRX levels were significantly increased in patients with AAA relative to healthy subjects (50+/-6 ng/ml vs. 26+/-3 ng/ml, p<0.05). These results were validated in a second independent group of patients. Moreover, a positive correlation between TRX and AAA size (rho=0.5, p<0.001) was observed. Finally, in AAA samples with follow-up, TRX was positively associated to aneurismal growth rate (rho=0.25, p=0.027). CONCLUSIONS: TRX release is increased in the luminal part of AAA and TRX serum levels are increased in AAA patients compared with healthy subjects. TRX levels correlates with AAA size and expansion, suggesting its potential role as a biomarker of AAA evolution.
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Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Estresse Oxidativo , Tiorredoxinas/metabolismo , Idoso , Aorta Abdominal/patologia , Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/cirurgia , Biomarcadores/metabolismo , Western Blotting , Estudos de Casos e Controles , Meios de Cultivo Condicionados/metabolismo , Dinamarca , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Masculino , Espanha , Tiorredoxinas/sangue , Técnicas de Cultura de Tecidos , Regulação para CimaRESUMO
Although structural and functional changes of resistance arteries have been proposed to participate in arterial hypertension (HTA) outcome, not all therapies may correct these alterations, even if they normalize the blood pressure (BP). The aim of this study was to investigate the mechanisms of the protection afforded by the angiotensin receptor antagonist losartan in resistance arteries from patients with essential HTA. In all, 22 untreated hypertensive patients were randomized to receive losartan or amlodipine for 1 year and the morphological characteristics of resistance vessels from subcutaneous biopsies were evaluated. Protein expression of connective tissue growth factor (CTGF), transforming growth factor beta (TGF-beta), and collagens III and IV was detected by immunohistochemistry. In comparison with normotensive subjects, resistance arteries from hypertensive patients showed a significant media:lumen (M/L) ratio increment and a higher protein expression of CTGF, TGF-beta, and collagens. After 1 year of treatment, both losartan and amlodipine similarly controlled BP. However, M/L only decreased in patients under losartan treatment, whereas in the amlodipine-treated group this ratio continued to increase significantly. The administration of losartan prevented significant increments in CTGF, TGF-beta, and collagens in resistance arteries. By contrast, amlodipine-treated patients showed a higher vascular CTGF, TGF-beta, and collagen IV staining than before treatment. Our results show that the administration of losartan, but not amlodipine, to hypertensive patients improves structural abnormalities and prevents the production of CTGF and TGF-beta in small arteries, despite similar BP lowering. These data may explain the molecular mechanisms of the better vascular protection afforded by drugs interfering with the renin-angiotensin system.
Assuntos
Artérias/fisiopatologia , Hipertensão/tratamento farmacológico , Proteínas Imediatamente Precoces/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Losartan/uso terapêutico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Resistência Vascular/efeitos dos fármacos , Adulto , Anlodipino/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Artérias/patologia , Artérias/fisiologia , Fator de Crescimento do Tecido Conjuntivo , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
Introducción. Las estatinas mejoran la estabilidad de la placa al disminuir la actividad inflamatoria. Hemos analizado el efecto de un ciclo corto de tratamiento con altas dosis de atorvastatina sobre la inflamación de la placa de ateroma carotídea humana. Materiales y métodos. Veinte pacientes programados para endarterectomía carotídea electiva, y sin tratamiento previo con estatinas, fueron asignados aleatoriamente en el momento de la indicación quirúrgica para recibir atorvastatina 80 mg/día (n = 11) o no estatinas (n = 9) hasta el día de la cirugía (1 mes). En las placas extraídas durante la endarterectomía se analizaban el infiltrado de macrófagos, y la expresión de MCP-1 (monocyte chemoattractant protein-1) y ciclooxigenasa-2 (COX-2) por inmunohistoquímica. La activación de NF-kB se estudió con la técnica de Southwestern. Resultados. La atorvastatina disminuyó las concentraciones de colesterol total (118 ± 10 frente a 191 ± 10 mg/dl; p = 0,016) y de lipoproteínas de baja densidad (LDL) (63 ± 9 frente a 125 ± 9 mg/dl; p = 0,038), mientras que no hubo cambios en el grupo control. Los triglicéridos y las lipoproteínas de alta densidad (HDL) no variaron significativamente en ningún grupo. Las placas ateroscleróticas del grupo de atorvastatina presentaron una reducción significativa del infiltrado de macrófagos (2,5 ± 1% frente a 9,3 ± 2,4%; p < 0,05), y de la expresión de MCP-1 (11 ± 1% frente a 24 ± 4%; p < 0,05) y COX-2 (16 ± 2,3% frente a 34 ± 4,4%; p < 0,05). El número de núcleos con actividad de NF-kB era menor en las placas de los pacientes que recibieron atorvastatina que en los que no recibieron tratamiento (5.706 ± 1.260 frente a 8.063 ± 1.308; p < 0,05). Conclusiones. El tratamiento intensivo con atorvastatina disminuye la inflamación en las placas de aterosclerosis carotídea humana en sólo 1 mes (AU)
Introduction. Statins improve plaque stability by diminishing inflammatory activity. We analyzed the effect of short-term high-dose atorvastatin on plaque inflammation in human carotid atherosclerosis. Materials and methods. Twenty patients scheduled to undergo elective carotid endarterectomy without previous statin treatment were randomized at the time of surgical indication to receive either atorvastatin 80 mg/day (n = 11) or no statins (n = 9) until surgery (1 month later). Atherosclerotic plaques were analyzed by immunohistochemistry to investigate macrophage infiltrate, and expression of monocyte chemoattractant protein-1 (MCP-1) and cyclooxygenase-2 (COX-2). In addition, nuclear factor-kB (NF-kB) activity was studied by Southwestern histochemistry. Results. Atorvastatin decreased serum levels of total cholesterol (118 ± 10 versus 191 ± 10 mg/dl; p = 0.016) and low-density lipoprotein (63 ± 9 versus 125 ± 9 mg/dl; p = 0.038), while no changes were noted in the control group. Triglycerides and high-density lipoprotein showed no significant changes in either of the two groups. Carotid atherosclerotic plaques from the atorvastatin group demonstrated a significant reduction in macrophage infiltration (2.5 ± 1% versus 9.3 ± 2.4%; p < 0.05) and expression of MCP-1 (11 ± 1% versus 24 ± 4%; p < 0.05) and COX-2 (16 ± 2.3% versus 34 ± 4.4%; p < 0.05). The number of nuclei active for NF-kB was lower in plaques from patients that received atorvastatin than in those from the non-treated group (5,706 ± 1,260 versus 8063 ± 1,308; p < 0.05). Conclusions. Intensive atorvastatin therapy decreases inflammatory activity in human carotid atherosclerotic plaques in as little as 1 month (AU)
Assuntos
Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Humanos , Arteriosclerose/tratamento farmacológico , Doenças das Artérias Carótidas/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inflamação/tratamento farmacológico , Endarterectomia das CarótidasRESUMO
La enfermedad vascular, incluyendo la aterotrombosis, es la causa más frecuentede mortalidad en el mundo occidental. En los últimos años se han producido tremendosavances en el mejor conocimiento de la patogenia de esta enfermedad.Sin embargo, el tratamiento farmacológico actual reside en gran medida en la administraciónde inhibidores de la HMG-CoA reductasa (estainas) y los fármacosanti-hipertensivos, principalmente los bloqueantes de la angiotensina II. Los primeroshan demostrado su principal efecto en la enfermedad cardiovascular debidaa aterotrombosis y los segundos en la enfermedad hipertensiva. Sin embargo,datos recientes sugieren que ambas situaciones pueden mejorar con el empleo deambos tipos de fármacos
Cardiovascular disease, including atherothrombosis, is the most frequent causeof mortality in the Western World. In the last years, major advances have beenmade in the pathogenesis of this disease. Currently, the drugs most widely usedare the inhibitors of the HMG-CoA reductase (statins) and the antihypertensivedrugs, mainly angiotensin II blockers. The first group has been shown to be effectiveon cardiovascular disease due to atherothrombosis, and the second groupon hypertensive disease. Nevertheless, recent data suggest that these two situationscan improve with the concomitant use of both drugs