RESUMO
BACKGROUND: Carotid atherosclerosis represents one of the complications of diabetes mellitus. In particular, plaque instability contributes to disease progression and stroke incidence. High mobility group box-1 (HMGB1) is a nuclear protein involved in promotion and progression of atherosclerosis and cardiovascular diseases. The aim of this study was to analyze the relationship between HMGB1 serum levels, main inflammatory cytokines, the presence of internal carotid stenosis and unstable plaque in a diabetic population. RESEARCH DESIGN AND METHODS: We studied 873 diabetic patients, including 347 patients with internal carotid artery stenosis (ICAS) who underwent carotid endarterectomy and 526 diabetic patients without internal carotid artery stenosis (WICAS). At baseline, HMGB1 and the main inflammatory cytokines serum levels were evaluated. For ICAS patients, the histological features of carotid plaque were also collected to differentiate them in patients with stable or unstable atherosclerotic lesions. RESULTS: We found that HMGB1 serum levels, osteoprotegerin, high-sensitivity C-reactive protein, tumor necrosis factor-alpha and interleukin-6, were significantly higher in diabetic ICAS patients compared to diabetic WICAS patients. Among ICAS patients, individuals with unstable plaque had higher levels of these cytokines, compared to patients with stable plaque. A multivariable stepwise logistic regression analysis showed that HMGB1 and osteoprotegerin remained independently associated with unstable plaque in ICAS patients. CONCLUSIONS: The present study demonstrated that HMGB1 is an independent risk factor for carotid plaque vulnerability in an Italian population with diabetes mellitus, representing a promising biomarker of carotid plaque instability and a possible molecular target to treat unstable carotid plaques and to prevent stroke.
Assuntos
Estenose das Carótidas/sangue , Diabetes Mellitus Tipo 2/sangue , Proteína HMGB1/sangue , Placa Aterosclerótica , Idoso , Biomarcadores/sangue , Proteína C-Reativa/análise , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/epidemiologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/sangue , Itália/epidemiologia , Masculino , Osteoprotegerina/sangue , Prognóstico , Medição de Risco , Fatores de Risco , Ruptura Espontânea , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: High mobility group box-1 (HMGB-1) is a nuclear protein also acting as inflammatory mediator, whilst osteoprotegerin (OPG), member of tumor necrosis factor receptor superfamily, is indicated as marker of vascular calcification. Peripheral artery disease (PAD) and type 2 diabetes (T2D) are clinical conditions characterized by elevated serum inflammatory markers and vascular calcification enhancement. The aim of this study was to investigate the potential role of HMGB-1, OPG and several inflammatory mediators such as C-reactive protein (HsCRP), tumor necrosis factor-alpha and interleukin-6 (IL-6) on the presence and severity of peripheral artery disease in patients with T2D. METHODS: In this retrospective observational study, we have analyzed HMGB-1, OPG and inflammatory cytokines serum levels in 1393 type 2 diabetic patients with PAD and without PAD (WPAD). RESULTS: HMGB-1 (7.89 ± 15.23 ng/mL), OPG (6.54 ± 7.76 pmol/L), HsCRP (15.6 ± 14.4 mg/L) and IL-6 (56.1 ± 28.6 pg/mL) serum levels were significantly higher in patients with PAD than in those WPAD (3.02 ± 8.12 ng/mL, P Ë 0.001; 2.98 ± 2.01 pmol/L, P < 0.001; 7.05 ± 4.4 mg/L, P < 0.001; 37.5 ± 20.2 pg/mL, P < 0.001 respectively). Moreover HMGB-1 (P < 0.001), OPG (P < 0.001), HsCRP (P < 0.001) and IL-6 (P < 0.001) serum levels were positively correlated with clinical severity of PAD. HMGB-1 (adjusted OR 12.32; 95% CI 3.56-23.54, P = 0.023) and OPG (adjusted OR 3.53; 95% CI 1.54-6.15, P = 0.019) resulted independent determinants of PAD in patients with T2D after adjusting for the conventional cardiovascular risk factor and established inflammatory mediators. CONCLUSIONS: In T2D patients HMGB-1 and OPG serum levels are higher in patients affected by PAD and independently associated with its occurrence and clinical severity.
Assuntos
Biomarcadores/sangue , Proteína HMGB1/sangue , Osteoprotegerina/sangue , Doença Arterial Periférica/complicações , Fator de Necrose Tumoral alfa/sangue , Idoso , Proteína C-Reativa/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Estudos Retrospectivos , Fatores de Risco , Calcificação Vascular/complicaçõesRESUMO
BACKGROUND: The object of this study was to investigate the potential role of FGF23 on plaque stability in type 2 diabetic patients with internal carotid artery stenosis. METHODS: In this retrospective observational study, we analyzed FGF23 serum level in 361 type 2 diabetic patients with internal carotid artery stenosis undergoing carotid endarterectomy and in 598 diabetic controls without carotid atherosclerosis. RESULTS: We found that FGF23 median serum levels was significantly higher in patients than in diabetic controls [67.7 (59.5-77.8) pg/mL and 43.89 (37.5-50.4), P < 0.001] and was significantly and independently associated with unstable plaque in patients with internal carotid artery stenosis [OR, 5,71 (95% CI, 2.09-15.29]. CONCLUSIONS: We have found, for the first time, that FGF23 could be associated with unstable plaque in type 2 diabetic patients with internal carotid artery stenosis.
Assuntos
Artéria Carótida Interna , Estenose das Carótidas/sangue , Diabetes Mellitus Tipo 2/sangue , Fatores de Crescimento de Fibroblastos/sangue , Placa Aterosclerótica/sangue , Idoso , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/cirurgia , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/cirurgia , Diabetes Mellitus Tipo 2/complicações , Endarterectomia das Carótidas , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Masculino , Placa Aterosclerótica/complicações , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/cirurgia , Estudos Retrospectivos , Ultrassonografia DopplerRESUMO
OBJECTIVE: Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Unstable atherosclerotic plaques are characterized by a large necrotic core. In this study we investigated the distribution and interaction between gene polymorphisms encoding proinflammatory molecules in an Italian population with internal carotid artery stenosis (ICAS). We also evaluated whether reciprocal interaction between these gene polymorphisms increased the risk of plaque vulnerability. METHODS: In this genetic association study, 11 proinflammatory gene polymorphisms were analyzed in 933 individuals comprising 344 patients with ICAS who underwent carotid endarterectomy and 589 controls without ultrasound evidence of atherosclerosis or intimal thickening. RESULTS: We found that interleukin (IL) 6 (IL-6), IL-1ß, monocyte chemoattractant protein-1 (CCL2) macrophage inflammatory protein-1α (CCL3), E-selectin (SELE), intercellular adhesion molecule 1 (ICAM1), and matrix metalloproteinase-3 (MMP-3), and 9 (MMP-9) gene variants were independently and significantly associated with ICAS. The association remained significant even after the Bonferroni correction. We also found a genetic profile associated with different risks for ICAS, depending on the number of high-risk genotypes simultaneously present in an individual. Furthermore, proinflammatory genetic profiles are significantly more common in individuals with unstable carotid plaque. CONCLUSIONS: Our study shows, for the first time, a reciprocal interaction between proinflammatory genotypes for the development and progression of ICAS.
Assuntos
Artéria Carótida Interna/patologia , Estenose das Carótidas/genética , Mediadores da Inflamação , Inflamação/genética , Placa Aterosclerótica , Polimorfismo de Nucleotídeo Único , Idoso , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/cirurgia , Espessura Intima-Media Carotídea , Estenose das Carótidas/diagnóstico , Estenose das Carótidas/imunologia , Estenose das Carótidas/cirurgia , Estudos de Casos e Controles , Progressão da Doença , Endarterectomia das Carótidas , Feminino , Frequência do Gene , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Inflamação/diagnóstico por imagem , Inflamação/imunologia , Itália , Masculino , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco , Ruptura EspontâneaRESUMO
AIMS: Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family and plays a role in atherosclerosis. OPG has been hypothesized to modulate vascular functions; however, its role in mediating atherosclerosis is controversial. Epidemiological data in patients with cardiovascular disease (CVD) indicate that OPG serum levels are associated with several inflammatory markers, myocardial infarction events, and calcium scores, suggesting that OPG may be causative for CVD. METHODS: The present study aimed to evaluate whether the OPG gene (TNFRSF11B) polymorphisms are involved in the development of peripheral arterial occlusive disease (PAOD) and critical limb ischemia (CLI) in patients with type 2 diabetes. This genetic association study included 402 diabetic patients (139 males and 263 females) with peripheral arterial occlusive disease and 567 diabetic subjects without peripheral arterial occlusive disease (208 males and 359 females). The T245G, T950C, and G1181C polymorphisms of the OPG gene were analyzed by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: We found that the T245G, T950C, and G1181C gene polymorphisms of the OPG gene were significantly (27.9 vs. 12.2 %, P < 0.01; 33.6 vs. 10.4 %, P < 0.01 and 24.4 vs. 12.7 %, P < 0.01, respectively) and independently (adjusted OR 4.97 (3.12-6.91), OR 7.02 (4.96-11.67), and OR 2.85 (1.95-4.02), respectively) associated with PAOD. We also found that these three polymorphisms act synergistically in patients with PAOD and are associated with different levels of risk for PAOD and CLI, depending on the number of high-risk genotypes carried concomitantly by a given individual. CONCLUSION: The TNFRSF11B gene polymorphisms under study are associated with PAOD, and synergistic effects between these genotypes might be potential markers for the presence and severity of atherosclerotic disorders.
Assuntos
Arteriopatias Oclusivas/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Extremidades/irrigação sanguínea , Isquemia/genética , Osteoprotegerina/genética , Polimorfismo de Nucleotídeo Único , Idoso , Arteriopatias Oclusivas/epidemiologia , Aterosclerose/epidemiologia , Aterosclerose/genética , Diabetes Mellitus Tipo 2/epidemiologia , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Isquemia/epidemiologia , Masculino , Fatores de RiscoRESUMO
BACKGROUND: A number of studies associate Alzheimer's disease (AD) with APOE polymorphism and alleles which favor the increased expression of immunological mediators such as cytokines or acute-phase proteins. OBJECTIVE: In this study we evaluated the distribution of a set of functionally important polymorphisms of genes encoding prototypical inflammatory molecules in individuals with AD. We also investigated whether a synergistic effect of these proinflammatory gene polymorphisms on the risk of AD could be hypothesized. METHODS: In a genetic association study that included 533 AD patients and 713 controls, the following gene polymorphisms were analyzed: C-reactive protein (CRP) 1059 G/C, interleukin 6 (IL6) -174 G/C, interleukin 1ß (IL1B) -31 T/C, tumor necrosis factor α (TNF-α) -308 G/A, macrophage migration inhibitory factor (MIF) -173 G/C, monocyte chemoattractant protein 1 (CCL2) -2518 A/G, intercellular adhesion molecule 1 (ICAM1) 469 E/K, E-selectin (SELE) Ser128Arg, macrophage inflammatory protein 1α (CCL3) -906 T/A, matrix metalloproteinase 3 (MMP3) -1171 5A/6A and matrix metalloproteinase 9 (MMP9) -1562 C/T. RESULTS: We found that IL6, IL1B, CCL2, CCL3, SELE, ICAM1, MMP3, and MMP9 gene polymorphisms were significantly and independently associated with AD. The association remained significant even after the Bonferroni correction. We also found that these proinflammatory polymorphisms were associated with different levels of risk for AD, depending on the number of high-risk genotypes concomitantly carried by a given individual. CONCLUSION: Proinflammatory genotypes might influence the development and progression of AD exerting a potential synergistic effect.
Assuntos
Doença de Alzheimer/genética , Polimorfismo Genético , Idoso , Doença de Alzheimer/diagnóstico , Antígenos CD/genética , Proteína C-Reativa/genética , Citocinas/genética , Feminino , Estudos de Associação Genética , Humanos , Inflamação/genética , Masculino , Metaloproteinase 1 da Matriz/genética , Fatores de RiscoRESUMO
BACKGROUND/OBJECTIVES: Cilostazol has been found to be effective for the treatment of intermittent claudication (IC). This compound has several beneficial effects on platelet aggregation, serum lipids and endothelial cells, but how these might relate to improvements in walking is not entirely understood. The aim of this work was to investigate the effects of cilostazol on angiogenic response in a murine model of peripheral ischemia and to clarify the underlying molecular mechanisms of that response. METHODS: We studied ischemia-induced neovascularization in the ischemic hindlimb of cilostazol-treated and untreated control mice. RESULTS: We found that the perfusion recovery was significantly improved in treated compared with control mice. Interestingly, there was a higher level of circulating endothelial progenitor cells (EPCs) in mice treated with cilostazol than in untreated mice. Furthermore, cilostazol administration resulted in upregulation of granulocyte colony-stimulating factor (G-CSF) and vascular endothelial growth factor (VEGF) in the ischemic muscle of treated mice. Finally, inhibiting VEGF activity significantly reduced cilostazol-induced angiogenesis. CONCLUSIONS: The results of this study show that cilostazol administration enhances collateral blood flow in the ischemic hindlimbs of mice through a VEGF-dependent mechanism. These data may help to explain the beneficial effects that this drug has on patients with peripheral arterial disease (PAD) and IC.
Assuntos
Isquemia/tratamento farmacológico , Isquemia/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Tetrazóis/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/biossíntese , Vasodilatadores/uso terapêutico , Animais , Cilostazol , Modelos Animais de Doenças , Membro Posterior/irrigação sanguínea , Membro Posterior/efeitos dos fármacos , Membro Posterior/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/fisiologia , Tetrazóis/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , Vasodilatadores/farmacologiaRESUMO
Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family and plays a role in atherosclerosis. The present study aimed to evaluate whether OPG gene (TNFRSF11B) polymorphisms are involved in ischemic stroke in an Italian population with diabetes. Participants in a retrospective case-control study included 364 diabetic patients (180 males, 184 females) with history of ischemic stroke and 492 diabetic subjects without history of ischemic stroke (252 males, 240 females). The T245G, T950C, and G1181C polymorphisms of the OPG gene were analyzed by polymerase chain reaction and restriction fragment length polymorphism. We found that the T245G, T950C, and G1181C gene polymorphisms of the OPG gene were significantly (34.1 vs. 9.5 %, P < 0.0001; 30.8 vs. 6.3 %, P < 0.0001 and 26.4 vs. 11.6 % P < 0.0001, respectively) and independently (adjusted OR 5.15 [3.46-7.68], OR 6.63 [4.26-10.31], and OR 3.03 [2.04-4.50], respectively) associated with history of ischemic stroke. We also found that these three polymorphisms act synergistically in patients with stroke history. The TNFRSF11B gene polymorphisms studied are associated with history of ischemic stroke and synergistic effects between these genotypes might be potential markers for cerebrovascular disorders.
Assuntos
Complicações do Diabetes/genética , Osteoprotegerina/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/genética , Idoso , Sequência de Bases , Estudos de Casos e Controles , DNA/genética , Feminino , Estudos de Associação Genética , Humanos , Itália , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND AND PURPOSE: Osteoprotegerin (OPG) is a secretory glycoprotein which belongs to the tumor necrosis factor receptor family. Various mechanisms have been suggested by which calcification might alter atherosclerotic plaque stability, but the significance of this intimal calcification is controversial. High concentrations of OPG have been associated with the presence of vascular and cardiovascular diseases. This study was designed to assess the association between gene polymorphisms of the OPG gene (TNFRSF11B), the serum OPG level, and plaque stability in patients with carotid atherosclerosis. METHODS: We studied 177 patients with internal carotid artery stenosis who underwent carotid endarterectomy and also 303 controls. Carotid endarterectomy samples removed from patients were assessed by immunohistochemistry. Concentrations of OPG were measured and gene polymorphisms were examined by polymerase chain reaction and restriction enzyme analysis and were compared, initially between patients with carotid atherosclerosis and controls, and subsequently between stable and unstable carotid plaques. RESULTS: We found that the GG genotype of the T245G polymorphism, the CC genotype of the T950C polymorphism, and the CC genotype of the G1181C polymorphism were significantly higher in patients with carotid plaque than in controls (21.5% versus 10.9% , P<0.01; 15.8% versus 7.6%, P<0.01; and 20.3% versus 10.9%, P<0.01, respectively) and that these polymorphisms were associated with high serum OPG levels (4.02 [3.07] versus 2.94 [1.81] pmol/L; P<0.01), which were significantly higher in patients with unstable atherosclerotic plaques (5.86 [4.02] versus 3.53 [1.87] pmol/L; P<0.01). CONCLUSIONS: The TNFRSF11B gene polymorphisms studied are associated with high serum OPG levels and might be potential markers for plaque instability.
Assuntos
Estenose das Carótidas/sangue , Estenose das Carótidas/genética , Predisposição Genética para Doença/genética , Osteoprotegerina/sangue , Osteoprotegerina/genética , Placa Aterosclerótica/sangue , Placa Aterosclerótica/genética , Polimorfismo Genético/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The aim of the present study was to investigate the role of GV (glycaemic variability) in diabetic vascular complications and to explore the molecular pathways modulated by glycaemic 'swings'. We developed a murine model. A total of 30 diabetic mice received once daily basal insulin administration plus two oral boluses of glucose solution (GV group, named 'V') and 30 diabetic mice received once daily basal insulin plus two oral boluses of saline solution (stable hyperglycaemia group, named 'S') for a period of 30 days. Glycaemia was measured eight times daily to detect GV. Finally, postischaemic vascularization, induced by hindlimb ischaemia 30 days after diabetes onset, was evaluated. We found that GV was significantly different between S and V groups, whereas no significant difference in the mean glycaemic values was detected. Laser Doppler perfusion imaging and histological analyses revealed that the ischaemia-induced angiogenesis was significantly impaired in V mice compared with S group, after ischaemic injury. In addition, immunostaining and Western blot analyses revealed that impaired angiogenic response in V mice occurred in association with reduced VEGF (vascular endothelial growth factor) production and decreased eNOS (endothelial nitric oxide synthase) and Akt (also called protein kinase B) phosphorylation. In conclusion, we describe a murine model of GV. GV causes an impairment of ischaemia-induced angiogenesis in diabetes, likely to be independent of changes in average blood glucose levels, and this impaired collateral vessel formation is associated with an alteration of the VEGF pathway.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Hiperglicemia/fisiopatologia , Isquemia/fisiopatologia , Neovascularização Patológica/fisiopatologia , Animais , Glicemia/metabolismo , Glicemia/fisiologia , Diabetes Mellitus Experimental/metabolismo , Angiopatias Diabéticas/metabolismo , Hiperglicemia/metabolismo , Isquemia/metabolismo , Isquemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Neovascularização Patológica/sangue , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
OBJECTIVE: High-mobility group box-1 (HMGB1) protein is a nuclear DNA-binding protein released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. Diabetic human and mouse tissues contain lower levels of HMGB1 than their normoglycemic counterparts. Deficient angiogenesis after ischemia contributes to worse outcomes of peripheral arterial disease in patients with diabetes. To test the hypothesis that HMGB1 enhances ischemia-induced angiogenesis in diabetes, we administered HMGB1 protein in a mouse hind limb ischemia model using diabetic mice. RESEARCH DESIGN AND METHODS: After the induction of diabetes by streptozotocin, we studied ischemia-induced neovascularization in the ischemic hind limb of normoglycemic, diabetic, and HMGB1-treated diabetic mice. RESULTS: We found that the perfusion recovery was significantly attenuated in diabetic mice compared with normoglycemic control mice. Interestingly, HMGB1 protein expression was lower in the ischemic tissue of diabetic mice than in normoglycemic mice. Furthermore, we observed that HMGB1 administration restored the blood flow recovery and capillary density in the ischemic muscle of diabetic mice, that this process was associated with the increased expression of vascular endothelial growth factor (VEGF), and that HMGB1-induced angiogenesis was significantly reduced by inhibiting VEGF activity. CONCLUSIONS: The results of this study show that endogenous HMGB1 is crucial for ischemia-induced angiogenesis in diabetic mice and that HMGB1 protein administration enhances collateral blood flow in the ischemic hind limbs of diabetic mice through a VEGF-dependent mechanism.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Proteína HMGB1/genética , Isquemia/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Velocidade do Fluxo Sanguíneo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Proteína HMGB1/fisiologia , Membro Posterior/irrigação sanguínea , Humanos , Isquemia/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/irrigação sanguínea , Neovascularização Patológica/genética , Neovascularização Fisiológica/genética , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Oxidative stress,which contributes to neuronal damage, is thought to be a pathophysiologicalmechanism of Alzheimer's disease (AD). Markers of oxidative stress may appear early in the preclinical, mild cognitive impairment (MCI) phase of AD.We investigated the interaction among enzymatic-derived oxysterols (24S-hydroxycholesterol and 27-hydroxycholesterol), markers of oxidative stress, including free radical-related oxysterols (7 hydroxycholesterol and 7-ketocholesterol), and vitamin E in AD patients and two amnestic MCI subtypes, amnestic single-domain MCI (a-MCI) subjects, and multidomain MCI (md-MCI) subjects, compared to healthy control subjects (HC). The study included 37 patients with AD, 24 with a-MCI, 29 with md-MCI, and 24 HC. Plasma assessments were made using isotope dilution-mass spectrometry. Although we found no significant change in free radical- or enzymatic-derived oxysterol concentrations in AD or MCI patients, vitamin E levels corrected for cholesterol were reduced in AD patients compared to HC. Results suggest that AD patients have upregulated cerebral oxidative stress or a nutritional deficit of vitamin E. The oxysterols investigated here are not useful markers for diagnosing AD or MCI.
Assuntos
Doença de Alzheimer/sangue , Transtornos Cognitivos/sangue , Hidroxicolesteróis/sangue , Estresse Oxidativo/fisiologia , Vitamina E/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Amnésia/sangue , Amnésia/diagnóstico , Amnésia/psicologia , Biomarcadores/sangue , Transtornos Cognitivos/classificação , Transtornos Cognitivos/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Atrial fibrillation is the most common arrhythmia in clinical practice, may coexist with conditions common to both cardiovascular and noncardiovascular diseases and is associated with considerable morbidity and mortality. Atrial fibrillation is often asymptomatic and diagnosed only when it has caused a potentially serious complication, such as an ischemic stroke. When atrial fibrillation has been identified, 2 objectives have to be addressed--the antiarrhythmic therapy based on rate control or rhythm control, and prevention of thromboembolism. A rhythm or rate control strategy can be chosen indifferently because they have comparable efficacy for the outcome measure of mortality, but the antithrombotic therapy is ever mandatory. The risk of stroke increases cumulatively with increasing age, previous transient ischemic attack or stroke, hypertension, diabetes mellitus, impaired left ventricular function and heart failure. Warfarin reduces the risk of stroke by about two thirds; and aspirin, by about one fifth, but its use must be weighted with the risk of bleeding. The risk of anticoagulant-associated hemorrhage increases with age, the presence of serious concomitant diseases, with poorly controlled hypertension and poorly controlled anticoagulation.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Antiarrítmicos/efeitos adversos , Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/patologia , Fibrinolíticos/efeitos adversos , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Tromboembolia/prevenção & controle , Varfarina/uso terapêuticoRESUMO
BACKGROUND: Type 2 diabetes mellitus (T2DM) is commonly associated with both microvascular and macrovascular complications and a strong correlation exists between glycaemic control and the incidence and progression of vascular complications. Pioglitazone, a Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligand indicated for therapy of type T2DM, induces vascular effects that seem to occur independently of glucose lowering. METHODS: By using a hindlimb ischemia murine model, in this study we have found that pioglitazone restores the blood flow recovery and capillary density in ischemic muscle of diabetic mice and that this process is associated with increased expression of Vascular Endothelial Growth Factor (VEGF). Importantly, these beneficial effects are abrogated when endogenous Akt is inhibited; furthermore, the direct activation of PPARgamma, with its selective agonist GW1929, does not restore blood flow recovery and capillary density. Finally, an important collateral vessel growth is obtained with combined treatment with pioglitazone and selective PPARgamma inhibitor GW9662. CONCLUSION: These data demonstrate that Akt-VEGF pathway is essential for ischemia-induced angiogenic effect of pioglitazone and that pioglitazone exerts this effect via a PPARgamma independent manner.
Assuntos
Circulação Colateral/efeitos dos fármacos , Membro Posterior/irrigação sanguínea , Isquemia/tratamento farmacológico , Proteína Oncogênica v-akt/fisiologia , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Anilidas/farmacologia , Animais , Benzofenonas/farmacologia , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Membro Posterior/patologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Isquemia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/antagonistas & inibidores , Pioglitazona , Transdução de Sinais/efeitos dos fármacos , Tiazolidinedionas/uso terapêutico , Tirosina/análogos & derivados , Tirosina/farmacologia , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Disarrangement in fatty acids and oxidative stress are features of cystic fibrosis. Cholesterol is very sensitive to oxidative stress. OBJECTIVES: The objectives were to examine whether cholesterol oxidation products are altered in cystic fibrosis and whether they are associated with fatty acids and with characteristics of the disease state. DESIGN: 7-Ketocholesterol and 7beta-hydroxycholesterol (prototype molecules of free radical-mediated cholesterol oxidation) and the fatty acid profile were assessed by mass spectrometry in patients and in sex- and age-matched control subjects. RESULTS: In a comparison with control subjects, mean (+/-SD) cholesterol oxidation was higher (7-ketocholesterol: 11.31 +/- 5.1 compared with 8.33 +/- 5.5 ng/mL, P = 0.03; 7beta-hydroxycholesterol: 14.5 +/- 6.8 compared with 9.7 +/- 4.1 ng/mL, P = 0.004), total saturated fatty acids were higher (31.90 +/- 1.93% compared with 30.31 +/- 0.98%, P < 0.001), monounsaturated fatty acids were higher (29.14 +/- 3.85% compared with 25.88 +/- 2.94%, P = 0.004), omega-6 (n-6) polyunsaturated fatty acids were lower (34.84 +/- 4.77 compared with 39.68 +/- 2.98%, P < 0.0001), and omega-3 (n-3) polyunsaturated fatty acids were comparable in patients with cystic fibrosis. Oxysterols were inversely associated with 24:0 and 18:2 omega-6 fatty acids but did not correlate with the increased oleic acid or with any of the omega-3 fatty acids. CONCLUSIONS: Cystic fibrosis is characterized by relevant cholesterol oxidation that is associated with an abnormal fatty acid profile. The interplay between oxysterols and fatty acids potentially provides insight into the biological mechanisms that underlie this complex disease.
Assuntos
Colesterol/metabolismo , Fibrose Cística/metabolismo , Ácidos Graxos/sangue , Estresse Oxidativo , Adolescente , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Ácidos Graxos/metabolismo , Feminino , Humanos , Hidroxicolesteróis/sangue , Cetocolesteróis/sangue , Masculino , Espectrometria de Massas , Oxirredução , Estatísticas não Paramétricas , Adulto JovemAssuntos
Linfedema/etiologia , Doenças da Unha/diagnóstico , Transtornos da Pigmentação/diagnóstico , Derrame Pleural/etiologia , Tornozelo/patologia , Diagnóstico Diferencial , Feminino , Humanos , Linfedema/diagnóstico , Pessoa de Meia-Idade , Doenças da Unha/patologia , Unhas Malformadas/diagnóstico , Unhas Malformadas/patologia , Transtornos da Pigmentação/patologia , Derrame Pleural/diagnóstico , SíndromeAssuntos
Fístula Arteriovenosa/diagnóstico por imagem , Neoplasias Femorais/diagnóstico por imagem , Fêmur/diagnóstico por imagem , Hemangioma/diagnóstico por imagem , Perna (Membro)/irrigação sanguínea , Tomografia Computadorizada por Raios X , Varizes/diagnóstico por imagem , Adulto , Fístula Arteriovenosa/complicações , Fístula Arteriovenosa/terapia , Embolização Terapêutica , Neoplasias Femorais/etiologia , Hemangioma/etiologia , Humanos , Masculino , Síndrome , Varizes/etiologiaRESUMO
Sonic hedgehog (Shh) is a morphogen-regulating crucial epithelial-mesenchymal interactions during embryonic development, but its signalling pathway is considered generally silent in post-natal life. In this study, we demonstrate that Shh is de novo expressed after injury and during regeneration of the adult skeletal muscle. Shh expression is followed by significant up-regulation of its receptor and target gene Ptc1 in injured and regenerating muscles. The reactivation of the Shh signalling pathway has an important regulatory role on injury-induced angiogenesis, as inhibition of Shh function results in impaired up-regulation of prototypical angiogenic agents, such as vascular endothelial growth factor (VEGF) and stromal-derived factor (SDF)-1alpha, decreased muscle blood flow and reduced capillary density after injury. In addition, Shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors Myf-5 and MyoD, decreases the up-regulation of insulin-like growth factor (IGF)-1 and reduces the number of myogenic satellite cells at injured site. Finally, Shh inhibition results in muscle fibrosis, increased inflammatory reaction and compromised motor functional recovery after injury. These data demonstrate that the Shh pathway is functionally important for adult skeletal muscle regeneration and displays pleiotropic angiogenic and myogenic potentials in post-natal life. These findings might constitute the foundation for new therapeutic approaches for muscular diseases in humans.
Assuntos
Proteínas Hedgehog/fisiologia , Músculo Esquelético/fisiologia , Neovascularização Fisiológica/fisiologia , Regeneração/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/irrigação sanguíneaRESUMO
BACKGROUND & AIMS: Vascular endothelial growth factor A (VEGF-A) mediates angiogenesis and might also have a role in inflammation and immunity. We examined whether VEGF-A signaling has a role in inflammatory bowel disease (IBD). METHODS: Expression levels of VEGF-A, and its receptors VEGFR-1 and VEGFR-2, were examined in samples from patients with IBD and compared with those of controls. The capacity of VEGF-A to induce angiogenesis was tested in human intestinal microvascular endothelial cells using cell-migration and matrigel tubule-formation assays. Levels of vascular cellular adhesion molecule-1 and intercellular adhesion molecule were measured by flow cytometry to determine induction of inflammation; neutrophil adhesion was also assayed. Expression patterns were determined in tissues from mice with dextran sulfate sodium (DSS)-induced colitis; the effects of VEGF-A overexpression and blockade were assessed in these mice by adenoviral transfer of VEGF-A and soluble VEGFR-1. Intestinal angiogenesis was measured by quantitative CD31 staining and leukocyte adhesion in vivo by intravital microscopy. RESULTS: Levels of VEGF-A and VEGFR-2 increased in samples from patients with IBD and colitic mice. VEGF-A induced angiogenesis of human intestinal microvascular endothelial cells in vitro as well as an inflammatory phenotype and adherence of neutrophils to intestinal endothelium. Overexpression of VEGF-A in mice with DSS-induced colitis worsened their condition, whereas overexpression of soluble VEGFR-1 had the opposite effect. Furthermore, overexpression of VEGF-A increased mucosal angiogenesis and stimulated leukocyte adhesion in vivo. CONCLUSIONS: VEGF-A appears to be a novel mediator of IBD by promoting intestinal angiogenesis and inflammation. Agents that block VEGF-A signaling might reduce intestinal inflammation in patients with IBD.