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3.
Toxicol Lett ; 316: 27-34, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513887

RESUMO

OBJECTIVE: Atherosclerosis is an autoimmune inflammatory disease that is closely associated with long-term exposure to fine particulate matter (PM2.5). CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a critical role in the regulation of T cell-mediated immune responses, and the depletion of CD4+CD25+Foxp3+ Tregs has been thought to play a prominent role in atherosclerosis. Therefore, we investigated the association between the CD4+CD25+Foxp3+ Tregs population and atherosclerotic development in ApoE-/- mice exposed to PM2.5. METHODS: We employed a real-world system to subject 40 ApoE-/- mice to ambient inhalation of PM2.5 (PM2.5 group, n = 20) or filtered air (FA group, n = 20) for 12 weeks. PM2.5 source apportionment, atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum level of inflammatory factors and lipid profiles, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen were quantified, respectively. RESULTS: The daily average concentration of PM2.5 was 57.4 ± 25.6 µg/m3. Atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum levels of IL-6, TNF-α, TC and LDL-C in the PM2.5 group increased significantly compared to the FA group. Whereas, serum levels of IL-10 and TGF-ß, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen in the PM2.5 group decreased significantly compared to the FA group. CONCLUSION: These results suggest that PM2.5 could accelerate the development of atherosclerosis in ApoE-/- mice, which is related to CD4+CD25+Foxp3+ Tregs down-regulation, as well as lipid deposition and systemic inflammation.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Material Particulado/toxicidade , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/imunologia , Aterosclerose/patologia , Biomarcadores/sangue , LDL-Colesterol/sangue , Citocinas/sangue , Modelos Animais de Doenças , Progressão da Doença , Fatores de Transcrição Forkhead/imunologia , Predisposição Genética para Doença , Mediadores da Inflamação/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Tamanho da Partícula , Fenótipo , Placa Aterosclerótica , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Fatores de Tempo
4.
Nutrients ; 11(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500172

RESUMO

A healthy dietary pattern and high quality nutrient intake reduce atherosclerotic cardiovascular disease risk. Red wine grape pomace (RWGP)-a rich natural source of dietary fiber and antioxidants-appears to be a potential functional food ingredient. The impact of a dietary supplementation with RWGP flour was evaluated in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice, a model of lethal ischemic heart disease. SR-B1 KO/ApoER61h/h mice were fed with atherogenic (high fat, cholesterol, and cholic acid, HFC) diet supplemented with: (a) 20% chow (HFC-Control), (b) 20% RWGP flour (HFC-RWGP), or (c) 10% chow/10% oat fiber (HFC-Fiber); and survival time was evaluated. In addition, SR-B1 KO/ApoER61h/h mice were fed for 7 or 14 days with HFC-Control or HFC-RWGP diets and plasma lipid levels, inflammation, oxidative damage, and antioxidant activity were measured. Atherosclerosis and myocardial damage were assessed by histology and magnetic resonance imaging, respectively. Supplementation with RWGP reduced premature death, changed TNF-α and IL-10 levels, and increased plasma antioxidant activity. Moreover, decreased atheromatous aortic and brachiocephalic plaque sizes and attenuated myocardial infarction and dysfunction were also observed. These results suggest that RWGP flour intake may be used as a non-pharmacological therapeutic approach, contributing to decreased progression of atherosclerosis, reduced coronary heart disease, and improved cardiovascular outcomes.


Assuntos
Antioxidantes/administração & dosagem , Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Suplementos Nutricionais , Frutas/química , Isquemia Miocárdica/prevenção & controle , Miocárdio/metabolismo , Estresse Oxidativo , Extratos Vegetais/administração & dosagem , Vitis/química , Ração Animal , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Dieta Aterogênica , Modelos Animais de Doenças , Feminino , Mediadores da Inflamação/sangue , Interleucina-10/sangue , Lipídeos/sangue , Masculino , Camundongos Knockout para ApoE , Isquemia Miocárdica/sangue , Isquemia Miocárdica/genética , Isquemia Miocárdica/patologia , Miocárdio/patologia , Extratos Vegetais/sangue , Extratos Vegetais/isolamento & purificação , Placa Aterosclerótica , Receptores Depuradores Classe B/deficiência , Receptores Depuradores Classe B/genética , Fator de Necrose Tumoral alfa/sangue
5.
Biomed Res Int ; 2019: 2931831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31392210

RESUMO

Background: The apolipoprotein E knockout (ApoE -/-) mouse model is well established for the study of terpenoids in the prevention of atherosclerosis. Studies investigating the clinical benefit of terpenoids in humans are scarce. This systematic review and meta-analysis evaluated the effects of terpenoid administration on atherosclerotic lesion area in ApoE -/- mice. Methods: A comprehensive literature search using PubMed, Embase, and the Cochrane Library databases was performed to identify studies that assessed the effects of terpenoids on atherosclerosis in ApoE -/- mice. The primary outcome was atherosclerotic lesion area, and study quality was estimated using SYRCLE's risk of bias tool. Results: The meta-analysis included 25 studies. Overall, terpenoids significantly reduced atherosclerotic lesion area when compared to vehicle control (P<0.00001; SMD: -0.55; 95% CI: -0.72, -0.39). In terpenoid type and dose subgroup analyses, sesquiterpenoid (P=0.002; SMD -0.93; 95% CI: -1.52, -0.34), diterpenoid (P=0.01; SMD: -0.30; 95% CI: -0.54, -0.06), triterpenoid (P<0.00001; SMD: -0.66; 95% CI: -0.94, -0.39), tetraterpenoid (P<0.0001; SMD: -1.81; 95% CI: -2.70, -0.91), low dose (P=0.0001; SMD: -0.51; 95% CI: -0.76, -0.25), medium dose (P<0.0001; SMD: -0.48; 95% CI: -0.72, -0.24), and high dose (P=0.002; SMD: -1.07; 95% CI: -1.74, -0.40) significantly decreased atherosclerotic lesion area when compared to vehicle control. PROSPERO register number is CRD42019121176. Conclusion: Sesquiterpenoid, diterpenoid, triterpenoid, and tetraterpenoid have potential as antiatherosclerotic agents with a wide range of doses. This systematic review provides a reference for research programs aimed at the development of terpenoid-based clinical drugs.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Terpenos/farmacologia , Animais , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Knockout para ApoE , PubMed
7.
Int J Cardiovasc Imaging ; 35(9): 1745-1753, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31312997

RESUMO

No data exist whether statins have robust anti-inflammatory effects of atherosclerotic plaques primarily during the early treatment period or continuously throughout use. This prospective three time point 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) study of the carotid artery assessed anti-inflammatory effects of statin during the early treatment period (initiation to 3 months) and late treatment period (3 months to 1 year) and their correlation with lipid and inflammatory profile changes during a year of therapy. Nine statin-naïve stable angina patients with inflammatory carotid plaques received 20 mg/day atorvastatin after undergoing initial 18F-FDG PET/CT scanning of carotid arteries and ascending thoracic aorta, and then completed serial 18F-FDG PET/CT imaging at 3 and 12 months whose data were analyzed. The primary outcome was the inter-scan percent change in target-to-background ratio (ΔTBR) within the index vessel. At 3 months of atorvastatin treatment, mean serum low-density lipoprotein cholesterol (LDL-C) level decreased by 36.4% to < 70 mg/dL (p = 0.001) and mean serum high-density lipoprotein cholesterol level increased to > 40 mg/dL (p = 0.041), with both maintained with no further reduction up to 1 year (p = 0.516 and 0.715, respectively) while mean serum high sensitivity C-reactive protein level only numerically decreased (p = 0.093). The index vessel ΔTBR showed continuous plaque inflammation reduction over 1 year, by 4.4% (p = 0.015) from the initiation to 3rd months and 6.2% (p = 0.009) from 3rd months to 1 year, respectively, without correlation with lipid profile changes. The ΔTBR of the bilateral carotid arteries and ascending aorta also continuously decreased from 3 months to 1 year. Three time point 18F-FDG PET/CT imaging demonstrates that statin's anti-inflammatory effect continues throughout its use up to 1 year, even though yielding stable below-target plasma LDL-C levels at 3 months.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aorta Torácica/efeitos dos fármacos , Doenças da Aorta/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Artérias Carótidas/efeitos dos fármacos , Doenças das Artérias Carótidas/tratamento farmacológico , Fluordesoxiglucose F18/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Idoso , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/patologia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/patologia , Aterosclerose/diagnóstico por imagem , Aterosclerose/patologia , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/patologia , LDL-Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
8.
J Vasc Res ; 56(4): 181-190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266015

RESUMO

BACKGROUND: Coagulant factor Xa inhibitors (XaIs) are prescribed for patients with atrial fibrillation for years. METHODS: Human umbilical venous endothelial cells (HUVECs) were cultured with or without (w/wo) a XaI (rivaroxaban) under high glucose (HG: 22 mM). Endothelial senescence was investigated by assessing senescence-associated-ß-galactosidase (SA-ß-gal), p53, and telomere length. Endothelial function and atherosclerosis were examined by nitric oxide-related-products (NOx: NO2- and NO3-), O2-, endothelial NO synthase (eNOS), NADPH oxidase (p22phox), and ICAM1. PAR1 (protease-activated receptor 1) and PAR2, which were reported to regulate eNOS phosphorylation, were inhibited by small interfering RNAs (siRNAs). Thirty-two male dyslipidemic type 2 diabetic rats (ZFDM LepRfa/fa) were fed a high-cholesterol diet w/wo XaI (50 µg/day/kg) for 1-4 weeks. RESULTS: SA-ß-gal, p53, p21, and p16INK4a were increased by HG and restored by XaI (50 nM) in HUVECs. XaI restored telomerase activity and preserved telomere length. XaI suppressed O2-, p22phox, and ICAM1 and restored NOx and eNOS. XaI decreased PAR1 following elevation by HG, which was confirmed by PAR1 siRNA and PAR2 siRNA. In in vivo experiments, plasma glucose, total cholesterol, and triglycerides were increased for 4 weeks but were not changed by XaI. XaI decreased SA-ß-gal and telomerase and preserved telomere length in the aortic endothelium. XaI activated eNOS, inhibited p22phox, increased plasma NOx, and decreased O2-. CONCLUSION: Rivaroxaban prevents replicative senescence in HUVECs and aortic endothelial cells in dyslipidemic diabetic mice. It restores endothelial function and prevents the progression of atherosclerosis.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Inibidores do Fator Xa/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Rivaroxabana/farmacologia , Animais , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/patologia , Glicemia/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/complicações , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Lipídeos/sangue , Óxido Nítrico/metabolismo , Ratos Zucker , Espécies Reativas de Oxigênio/metabolismo , Receptores Ativados por Proteinase/metabolismo , Transdução de Sinais , Telomerase/metabolismo
9.
Angiology ; 70(10): 969-977, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31064194

RESUMO

Aortic diameter and progression to thoracic aortic aneurysm are influenced by several factors. In this study, we investigated the association of alcohol consumption with aortic root and ascending aorta dilatation. In the context of the Corinthia study, we examined 1751 patients with echocardiography. Several demographic and clinical characteristics were recorded. Alcohol consumption was assessed based on a questionnaire of frequency, type, and quantity. Accordingly, patients were categorized as everyday alcohol consumers (EDACs) and as social drinkers (SoD). Everyday alcohol consumers were further categorized to group 1: 0 to 1 drink/d; group 2: 1 to 2 drinks/d; and group 3: ≥3 drinks/d. From the study population, 40% were categorized as EDAC and had an increased aortic root diameter (AoRD) and an elevated AoRD index compared with SoD. Interestingly, there was a stepwise increase in aortic root and ascending aorta diameter according to daily alcohol consumption. Specifically, patients consuming ≥3 drinks of alcohol/d had increased indexed aortic by 1.4 mm/m2 compared with SoD even after adjustment for possible confounders. Daily alcohol consumption is associated with increased aortic root diameter. These findings may have important clinical implications, especially in patients with borderline or dilated aortic root, and merit further investigation.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Aorta Torácica/patologia , Doenças da Aorta/patologia , Cardiopatias Congênitas/patologia , Doenças das Valvas Cardíacas/patologia , Adulto , Idoso , Consumo de Bebidas Alcoólicas/metabolismo , Aorta Torácica/diagnóstico por imagem , Doenças da Aorta/fisiopatologia , Valva Aórtica/patologia , Valva Aórtica/fisiopatologia , Dilatação Patológica/patologia , Dilatação Patológica/fisiopatologia , Ecocardiografia Transesofagiana/métodos , Feminino , Cardiopatias Congênitas/fisiopatologia , Doenças das Valvas Cardíacas/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco
10.
J Vasc Res ; 56(1): 28-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947215

RESUMO

BACKGROUND: Hypertension is a major risk factor for atherosclerotic disease. However, it is still not clear whether mechanical stress caused by hypertension directly affects the atherosclerotic development in the aorta and coronary arteries. OBJECTIVES AND METHODS: We generated a hypertensive (HTN) rabbit model by surgical removal of the left kidney and partial ligation of the right renal artery. After a 16-week cholesterol diet, we compared aortic and coronary atherosclerosis of HTN rabbits with those of normotensive rabbits. RESULTS: Hypertension did not affect lipid and apolipoprotein levels in plasma but led to a 3.0-fold increase in aortic atherosclerosis and a 1.7-fold increase in coronary atherosclerosis compared with control rabbits. Enhanced atherosclerosis in HTN rabbits was caused by significant increases in macrophages and smooth muscle cells in the lesions. Furthermore, oxidized LDL contents in the lesions were significantly increased in HTN rabbits. In addition, HTN rabbits exhibited prominent hyaline arteriolosclerosis in coronary arterioles. CONCLUSIONS: These results indicate that hyper tension not only enhances atherosclerosis in large arteries including the aorta and coronary arteries but also affects hyaline arteriolosclerosis in small arteries.


Assuntos
Doenças da Aorta/etiologia , Aterosclerose/etiologia , Colesterol na Dieta , Doença da Artéria Coronariana/etiologia , Hipercolesterolemia/complicações , Hipertensão Renovascular/complicações , Animais , Doenças da Aorta/sangue , Doenças da Aorta/patologia , Doenças da Aorta/fisiopatologia , Pressão Arterial , Artérias/metabolismo , Artérias/patologia , Aterosclerose/sangue , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Hialina/metabolismo , Hipercolesterolemia/sangue , Hipertensão Renovascular/fisiopatologia , Lipoproteínas LDL/metabolismo , Masculino , Placa Aterosclerótica , Coelhos , Fatores de Risco , Fatores de Tempo
11.
J Stroke Cerebrovasc Dis ; 28(6): 1586-1596, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30928215

RESUMO

BACKGROUND: Complex aortic plaque is a potential cause of acute ischemic cerebrovascular disease, which needs timely identification. Also as a marker for systemic atherosclerosis, complex aortic plaque may be indicated by significant (≥50%) cervicocephalic atherosclerotic stenosis. We aimed at examining whether age ranges would influence their association to more accurately estimate the risk of having complex aortic plaque in acute ischemic cerebrovascular disease. METHODS: Aortic arch and cervicocephalic arteries were simultaneously evaluated using computed tomography angiography. Middle-aged (45-64 years) and old-aged (65-85 years) acute ischemic cerebrovascular disease patients were divided into 2 groups according to whether there was an aortic arch plaque with thickness of greater than or equal to 4 mm or associated ulcerations or mural thrombus. RESULTS: Old-aged patients (n = 107) had a higher prevalence of complex aortic plaque (67.3% versus 30.9%, P < .001) than those middle aged (n = 178). Among middle-aged patients, the presence of extracranial significant atherosclerotic stenosis (adjusted odd ratio = 2.89, 95% confidence interval: 1.42-5.86) rather than intracranial ones independently predicted complex aortic plaque. Regarding the extent of significant cervicocephalic atherosclerotic stenosis, the presence of multi-segment, bilateral, simultaneous extracranial and intracranial, and simultaneous anterior and posterior circulation ones were independent indicators for complex aortic plaque in the middle-aged subgroup (adjusted odd ratio = 2.42, 2.05, 2.26, 2.14, respectively). By contrast, no statistical correlation of complex aortic plaque and significant cervicocephalic atherosclerotic stenosis was found among old-aged patients. CONCLUSION: Considering the ranges of age was important to more precisely predict complex aortic plaque with significant cervicocephalic atherosclerotic stenosis in acute ischemic cerebrovascular disease.


Assuntos
Aorta Torácica/patologia , Doenças da Aorta/epidemiologia , Aterosclerose/epidemiologia , Isquemia Encefálica/epidemiologia , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/epidemiologia , Artérias Cerebrais/patologia , Arteriosclerose Intracraniana/epidemiologia , Placa Aterosclerótica , Acidente Vascular Cerebral/epidemiologia , Artéria Vertebral/patologia , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Aorta Torácica/diagnóstico por imagem , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/patologia , Aortografia/métodos , Aterosclerose/diagnóstico por imagem , Aterosclerose/patologia , Isquemia Encefálica/diagnóstico , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/patologia , Artérias Cerebrais/diagnóstico por imagem , China/epidemiologia , Angiografia por Tomografia Computadorizada , Estudos Transversais , Feminino , Humanos , Arteriosclerose Intracraniana/diagnóstico por imagem , Arteriosclerose Intracraniana/patologia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Dados Preliminares , Prevalência , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Artéria Vertebral/diagnóstico por imagem
12.
Can Assoc Radiol J ; 70(2): 204-209, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30922788

RESUMO

PURPOSE: The purpose of this study is to introduce the aortic bulge sign, a finding observed retrospectively on computed tomography prior to the acute presentation of aortoenteric fistula, and to determine its interobserver reliability. METHODS: Following research ethics board approval, all cases of aortoenteric fistula at our institution occurring from 2011-2015 were identified retrospectively. All previous computed tomography images of patients who eventually developed aortoenteric fistula were reviewed by a single observer for the presence of a potentially predictive finding of fistulization, the aortic bulge sign. These previous images were then combined with age and sex matched controls into a case bank. Eight radiology residents and staff were instructed in observing the aortic bulge sign. These observers then reviewed the case bank in a blinded analysis to determine the interobserver reliability of this finding. RESULTS: Fourteen cases of aortoenteric were identified. The average patient age was 70.71 years with a male-to-female ratio of 11:3. Eleven patients had previous computed tomography images available for review. With blinded analysis by multiple observers, the aortic bulge sign was identified with greater than 80% agreement in six of 11 cases (66.67%). Fleiss' kappa was calculated at k = 0.60 (95% confidence interval 0.50-0.69), corresponding to moderate-to-substantial interobserver agreement. CONCLUSIONS: The aortic bulge sign has been retrospectively identified as a promising computed tomography finding of eventual aortoenteric fistula prior to acute presentation. Further study is required to determine the diagnostic value of this sign.


Assuntos
Aorta/diagnóstico por imagem , Aorta/patologia , Doenças da Aorta/diagnóstico por imagem , Fístula do Sistema Digestório/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Fístula Vascular/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Doenças da Aorta/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos
14.
Am J Med Sci ; 357(4): 323-332, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30904048

RESUMO

BACKGROUND: This study assessed the effect of ibandronate (IBN), a farnesyl pyrophosphate synthase (FPPS) inhibitor, on vascular remodeling in diabetic rats. METHODS: A rat model of diabetes was induced by a high-fat and high-sugar diet combined with a small dose of streptozotocin. The diabetic rats received 5 µg/kg of ibandronate solution or normal saline subcutaneously every morning for 16 weeks. The morphology of the thoracic aorta was assessed by hematoxylin and eosin and Masson's trichrome staining techniques. Gene expression levels of connective tissue growth factor (CTGF) and FPPS were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. CTGF and FPPS protein levels were determined by Western blotting analysis. RESULTS: Rats with diabetes mellitus showed moderate hyperglycemia, insulin resistance, hyperlipidemia and thoracic aortic fibrosis. FPPS was significantly upregulated in the thoracic aorta from diabetic animals. Interestingly, IBN treatment for 16 weeks alleviated the diabetes-induced histopathologic changes in the thoracic aortic wall and reduced CTGF protein and mRNA levels. CONCLUSIONS: These findings provided evidence that FPPS is involved in thoracic aortic fibrosis in diabetic rats. Meanwhile, IBN could alleviate vascular remodeling in diabetic animals.


Assuntos
Aorta Torácica/patologia , Doenças da Aorta/tratamento farmacológico , Fibrose/tratamento farmacológico , Geraniltranstransferase/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Ácido Ibandrônico/farmacologia , Animais , Doenças da Aorta/patologia , Diabetes Mellitus Experimental/etiologia , Fibrose/patologia , Masculino , Ratos , Ratos Sprague-Dawley
15.
Cardiovasc Pathol ; 40: 59-64, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30904751

RESUMO

OBJECTIVES: The purpose of this study was to evaluate the microscopic structural abnormalities of the ascending aorta in infants with Tetralogy of Fallot (ToF) and compare them with aortic samples from control group of small children that died of other diseases. We aimed at identification of the specific histopathological changes associated with ToF and correlation of the severity of these changes with time to surgery and mean levels of saturation in the ToF group, and age at death in control group. METHODS: The full-thickness ascending aortic wall sample was taken from 23 children with ToF at the time of surgical reconstruction (age spread 2 to 19 months) and evaluated by light microscopy. Corresponding samples were taken from 16 cadaverous cases of children with other diseases (0-76 months). The assessed morphological variables included elastic fiber fragmentation/loss, thinning and disorganisation, presence of laminar medial necrosis, intralamellar and translamellar mucoid extracellular matrix accumulations, smooth muscle cell disorganisation, presence of fibrosis, calcifications and neovascularisation and finally grade of overall medial degeneration. RESULTS: No difference was found between the two groups in the individual morphological variables. However, there was a difference in the distribution of the grades of the overall medial degeneration (P = .016). ToF group showed uniform mild degenerative changes, whereas control group harboured spectrum of changes ranging from normal to moderate. The presence of the given histopathological changes and their severity were associated neither with age at surgery or mean levels of saturation in ToF group, nor with the age at death in the control group. CONCLUSIONS: This study emphasizes the histopathological assessment of the bioptic samples of the ascending aorta during the surgical repair of ToF, since the patients demonstrating moderate or severe degenerative changes already in the early childhood may be in increased risk of the subsequent late complications.


Assuntos
Aorta/patologia , Doenças da Aorta/patologia , Procedimentos Cirúrgicos Cardíacos , Tetralogia de Fallot/cirurgia , Fatores Etários , Doenças da Aorta/mortalidade , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/mortalidade , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Tetralogia de Fallot/mortalidade , Tetralogia de Fallot/patologia
17.
BMJ Case Rep ; 12(3)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872337

RESUMO

Paraneoplastic autoimmune encephalopathic syndromes have been described most often in association with small cell lung cancer or breast cancer, tumours of the ovaries, testes, lymphoma and thymoma. Antibodies associated with paraneoplastic encephalopathies are, among others, anti-Hu, anti-Ma2 and, in part, anti-N-methyl-D-aspartate(NMDA)-receptor antibodies. Here, we present the case of a 72-year-old patient hospitalised due to progressive cognitive decline and disorientation. Diagnostic workup revealed paraneoplastic anti-amphiphysin associated limbic encephalitis on the basis of an aortic angiosarcoma with metastases to kidney, muscle and bones. Highly aggressive chemotherapy as well as immunosuppressive therapy and cytoreductive laparoscopic nephrectomy were initiated. However, follow-up revealed further tumour progress and a worsening of neurological symptoms.


Assuntos
Doenças da Aorta/complicações , Encefalite Límbica/diagnóstico , Proteínas do Tecido Nervoso/antagonistas & inibidores , Idoso , Doenças da Aorta/patologia , Neoplasias Ósseas/complicações , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Tratamento Farmacológico/métodos , Evolução Fatal , Hemangiossarcoma , Humanos , Imunossupressores/uso terapêutico , Neoplasias Renais/complicações , Neoplasias Renais/patologia , Neoplasias Renais/secundário , Neoplasias Renais/cirurgia , Encefalite Límbica/complicações , Encefalite Límbica/tratamento farmacológico , Encefalite Límbica/imunologia , Masculino , Neoplasias Musculares/complicações , Neoplasias Musculares/patologia , Neoplasias Musculares/secundário , Metástase Neoplásica/patologia , Nefrectomia/métodos , Proteínas do Tecido Nervoso/metabolismo
18.
Clin Sci (Lond) ; 133(5): 629-643, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30737255

RESUMO

Aims: The renin-angiotensin system (RAS) plays an important role in the pathophysiology of vascular diseases, especially as a mediator of inflammation and tissue remodelling. Alamandine (Ala1-angiotensin-(1-7)) is a new biologically active peptide from the RAS, interacting with Mas-related G-protein-coupled receptor member D. Although a growing number of studies reveal the cardioprotective effects of alamandine, there is a paucity of data on its participation in vascular remodelling associated events. In the present study, we investigated the effects of alamandine on ascending aorta remodelling after transverse aortic constriction (TAC) in mice. Methods and results: C57BL/6J male mice were divided into the following groups: Sham (sham-operated), TAC (operated) and TAC+ALA (operated and treated with alamandine-HPßCD (2-Hydroxypropyl-ß-cyclodextrin), 30 µg/kg/day, by gavage). Oral administration of alamandine for 14 days attenuated arterial remodelling by decreasing ascending aorta media layer thickness and the cells density in the adventitia induced by TAC. Alamandine administration attenuated ascending aorta fibrosis induced by TAC, through a reduction in the following parameters; total collagen deposition, expression collagen III and transforming growth factor-ß (TGF-ß) transcripts, matrix metalloproteinases (MMPs) activity and vascular expression of MMP-2. Importantly, alamandine decreased vascular expression of proinflammatory genes as CCL2, tumour necrosis factor α (TNF-α) and interleukin-1ß (IL-1ß), and was able to increase expression of MRC1 and FIZZ1, pro-resolution markers, after TAC surgery. Conclusion: Alamandine treatment attenuates vascular remodelling after TAC, at least in part, through anti-fibrotic and anti-inflammatory effects. Hence, this work opens new avenues for the use of this heptapeptide also as a therapeutic target for vascular disease.


Assuntos
Anti-Inflamatórios/farmacologia , Aorta Torácica/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Oligopeptídeos/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Doenças da Aorta/fisiopatologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose , Mediadores da Inflamação/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
19.
Nutr Metab Cardiovasc Dis ; 29(3): 306-315, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30738642

RESUMO

BACKGROUND AND AIMS: Heparin-binding EGF-like growth factor (HB-EGF) is a representative EGF family member that interacts with EGFR under diverse stress environment. Previously, we reported that the HB-EGF-targeting using antisense oligonucleotide (ASO) effectively suppressed an aortic aneurysm in the vessel wall and circulatory lipid levels. In this study, we further examined the effects of the HB-EGF ASO administration on the development of hyperlipidemia-associated atherosclerosis using an atherogenic mouse model. METHODS AND RESULTS: The male and female LDLR deficient mice under Western diet containing 21% fat and 0.2% cholesterol content were cotreated with control and HB-EGF ASOs for 12 weeks. We observed that the HB-EGF ASO administration effectively downregulated circulatory VLDL- and LDL-associated lipid levels in circulation; concordantly, the HB-EGF targeting effectively suppressed the development of atherosclerosis in the aorta. An EGFR blocker BIBX1382 administration suppressed the hepatic TG secretion rate, suggesting a positive role of the HB-EGF signaling for the hepatic VLDL production. We newly observed that there was a significant improvement of the insulin sensitivity by the HB-EGF ASO administration in a mouse model under the Western diet as demonstrated by the improvement of the glucose and insulin tolerances. CONCLUSION: The HB-EGF ASO administration effectively downregulated circulatory lipid levels by suppressing hepatic VLDL production rate, which leads to effective protection against atherosclerosis in the vascular wall.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Hiperlipidemias/prevenção & controle , Lipoproteínas VLDL/sangue , Oligonucleotídeos Antissenso/administração & dosagem , Animais , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Colesterol/sangue , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Células Hep G2 , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/genética , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos Knockout , Placa Aterosclerótica , Receptores de LDL/deficiência , Receptores de LDL/genética , Triglicerídeos/sangue
20.
Arterioscler Thromb Vasc Biol ; 39(3): 432-445, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30626205

RESUMO

Objective- Vascular smooth muscle cell (VSMC) transformation to an osteochondrogenic phenotype is an initial step toward arterial calcification, which is highly correlated with cardiovascular disease-related morbidity and mortality. TLR2 (Toll-like receptor 2) plays a pathogenic role in the development of vascular diseases, but its regulation in calcification of arteries and VSMCs remains unclear. We postulate that TLR2-mediated inflammation participates in mediating atherosclerotic arterial calcification and VSMC calcification. Approach and Results- We found that ApoE-/- Tlr2-/- genotype in mice suppressed high-fat diet-induced atherosclerotic plaques formation during initiation but progressively lost its preventative capacity, compared with ApoE-/- mice. However, TLR2 deficiency prohibited high-fat diet-induced advanced atherosclerotic calcification, chondrogenic metaplasia, and OPG (osteoprotegerin) downregulation in the calcified lesions. Incubation of VSMCs in a calcifying medium revealed that TLR2 agonists significantly increased VSMC calcification and chondrogenic differentiation. Furthermore, TLR2 deficiency suppressed TLR2 agonist-mediated VSMC chondrogenic differentiation and consequent calcification, which were triggered via the concerted actions of IL (interleukin)-6-mediated RANKL (receptor activator of nuclear factor κB ligand) induction and OPG suppression. Inhibition experiments with pharmacological inhibitors demonstrated that IL-6-mediated RANKL induction is signaled by p38 and ERK1/2 (extracellular signal-regulated kinase 1/2) pathways, whereas the OPG is suppressed via NF-κB (nuclear factor κB) dependent signaling mediated by ERK1/2. Conclusions- We concluded that on ligand binding, TLR2 activates p38 and ERK1/2 signaling to selectively modulate the upregulation of IL-6-mediated RANKL and downregulation of OPG. These signaling pathways act in concert to induce chondrogenic transdifferentiation of VSMCs, which in turn leads to vascular calcification during the pathogenesis of atherosclerosis.


Assuntos
Aterosclerose/patologia , Calcinose/metabolismo , Calcinose/patologia , Condrogênese/fisiologia , Interleucina-6/fisiologia , Sistema de Sinalização das MAP Quinases , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Osteoprotegerina/biossíntese , Ligante RANK/biossíntese , Receptor 2 Toll-Like/fisiologia , Animais , Doenças da Aorta/etiologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/prevenção & controle , Apolipoproteínas E/deficiência , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/prevenção & controle , Calcinose/genética , Células Cultivadas , Colesterol na Dieta/toxicidade , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/toxicidade , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Osteoprotegerina/genética , Ligante RANK/genética , Distribuição Aleatória
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