Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.980
Filtrar
1.
DNA Cell Biol ; 38(12): 1540-1556, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31730405

RESUMO

Abdominal aortic aneurysm (AAA) is a lethal vascular degenerative disease for the elderly, but current therapeutic options are limited. This study was to explore the molecular mechanisms of AAA to screen underlying treatment targets for AAA. The gene and microRNA (miRNA) expression profiles of human AAA were downloaded from Gene Expression Omnibus database under accession number GSE57691, GSE62179, and GSE63541. Differentially expressed genes (DEGs) and microRNAs (miRNAs; DEMs) were identified using the Linear Models for Microarray data method. Protein-protein interaction (PPI) network, module analysis, and miRNA-mRNA regulatory network analyses were performed to screen hub genes and miRNAs that regulated the hub genes. The Database for Annotation, Visualization and Integrated Discovery was used to predict the functions of genes. GEPIA and Tumor-miRNA-Pathway online software were used to validate the expressions of crucial DEMs and DEGs in other cancers, respectively. As a result, in the GSE57691 dataset, a total of 584 DEGs were found to be specific for AAA, 521 of which were used for constructing the PPI network. ACSS2 (acyl-CoA synthetase short-chain family member 2), GNG2 (G protein subunit gamma 2), and CXCL1 (C-X-C motif chemokine ligand 1) and CCR7 (C-C motif chemokine receptor 7) were believed to be hub genes by calculating their topological features in the PPI network. Upregulated GNG2 could interact with CXCL1 and CCR7 to involve in chemokine signaling pathway, while downregulated ACSS2 was associated with lipid biosynthetic process. In the miRNA-mRNA regulatory network, ACSS2 was found to be regulated by hsa-miR-15b; hsa-miR-30a could modulate the expression of GNG2. In line with our analysis in AAA, GNG2, ACSS2, hsa-miR-30a, and hsa-miR-15b were also confirmed to be significantly upregulated or downregulated in several cancer types. In conclusion, hsa-miR-30a-GNG2 and hsa-miR-15b-ACSS2 interaction pairs may represent novel mechanisms for explaining the pathogenesis of AAA. Targeted regulation of them may be potential strategies for treatment of AAA.


Assuntos
Acetato-CoA Ligase/metabolismo , Aneurisma da Aorta Abdominal/etiologia , Proteínas de Ligação ao GTP/metabolismo , Regulação Neoplásica da Expressão Gênica , Inflamação/complicações , MicroRNAs/genética , Acetato-CoA Ligase/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Biomarcadores Tumorais/genética , Biologia Computacional , Proteínas de Ligação ao GTP/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Inflamação/genética , Mapas de Interação de Proteínas
2.
J Vasc Res ; 56(5): 255-266, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31533112

RESUMO

INTRODUCTION: In spite of the great relevance of abdominal aortic aneurysm, its etiopathogenesis is not fully understood. The biomechanical and histological study of the aortic wall may contribute to this elucidation. METHODS: Seventy-five male Wistar rats were divided into 4 groups: control (CG), smoker (SG), diabetic (DG), and diabetic + smoker (DSG). The SG and DSG rats were exposed to cigarette smoke for 30 min/day, 5 days a week. Diabetes was induced by the intravenous injection of streptozotocin. After 16 weeks, the abdominal aorta was collected for biomechanical, histological, and matrix metalloproteinase 2 (MMP-2) activity analyses. RESULTS: The valid biomechanical tests of 52 specimens were analyzed: 11 in the CG, 10 in the DG, 16 in the SG, and 15 in the DSG. The biomechanical analysis of the fragments showed no differences between the control, DG, SG, and DSG. Collagen deposition also did not present a significant difference between the studied groups. The total count of elastic fibers was higher in diabetic rats (DG and DSG) than in the SG. The inflammatory response observed in all experimental groups was significantly more intense than in the CG. Compared to the DSG, MMP-2 activity showed a significant decrease in the DG. CONCLUSIONS: Resistance and elasticity did not present a difference between the CG and the DG, SG, and DSG. Compared to the CG, the total count of elastic fibers, fragmentation of the elastic lamina, pericellular matrix deposition, and cell loss/substitution in the tunica media showed significant alterations in the aortic walls of the DG, SG, and DSG. MMP-2 activity was lower in the DG aorta than in the DSG aorta.


Assuntos
Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/etiologia , Diabetes Mellitus Experimental/complicações , Fumaça/efeitos adversos , Produtos do Tabaco/efeitos adversos , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/fisiopatologia , Fenômenos Biomecânicos , Colágeno/metabolismo , Progressão da Doença , Tecido Elástico/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Ratos Wistar , Fluxo Sanguíneo Regional , Fatores de Risco , Estresse Mecânico , Fatores de Tempo
3.
Int J Mol Sci ; 20(16)2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31405245

RESUMO

Although abdominal aortic aneurysm (AAA) is a common vascular disease and is associated with high mortality, the full pathogenesis of AAA remains unknown to researchers. Abdominal aortic aneurysms and atherosclerosis are strongly related. Currently, it is more often suggested that development of AAA is not a result of atherosclerosis, however, individual factors can act independently or synergistically with atherosclerosis. One of such factors is low-density lipoprotein (LDL) and its oxidized form (oxLDL). It is known that oxLDL plays an important role in the pathogenesis of atherosclerosis, thus, we decided to examine oxLDL impact on the development of AAA by creating two models using Petri-nets. The first, full model, contains subprocess of LDL oxidation and all subprocesses in which it participates, while the second, reduced model, does not contain them. The analysis of such models can be based on t-invariants. They correspond to subprocesses which do not change the state of the modeled system. Moreover, the knockout analysis has been used to estimate how crucial a selected transition (representing elementary subprocess) is, based on the number of excluded subprocesses as a result of its knockout. The results of the analysis of our models show that oxLDL affects 55.84% of subprocesses related to AAA development, but the analysis of the nets based on knockouts and simulation has shown that the influence of oxLDL on enlargement and rupture of AAA is negligible.


Assuntos
Aneurisma da Aorta Abdominal/patologia , Aterosclerose/patologia , Lipoproteínas LDL/metabolismo , Algoritmos , Animais , Aneurisma da Aorta Abdominal/metabolismo , Aterosclerose/metabolismo , Modelos Animais de Doenças , Humanos , Modelos Biológicos
4.
J Vasc Res ; 56(5): 230-240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31307051

RESUMO

OBJECTIVE: The relationship between methionine (Met) and abdominal aortic aneurysm (AAA) has been previously demonstrated, but the mechanisms controlling this association remain unclear. This study investigated the potential contribution of hypermethioninemia (HMet) to the development of AAA. METHODS: A model of AAA was induced by intraluminal porcine pancreatic elastase (PPE) infusion in 60 male Sprague-Dawley rats divided into 4 groups (n = 15 per group). Met was supplied by intragastric administration (1 g/kg body weight/day) from 1 week before surgery until 4 weeks after surgery. The aortic diameter was measured by ultrasound. Aortas were collected 4 weeks after surgery and subjected to biochemical analysis, histological assays, and transmission electron microscopy. RESULTS: After 5 weeks of Met supplementation, HMet increased the dilation ratio of the HMet + PPE group, and hyperhomocysteinemia was also induced in HMet and HMet + PPE rats. Increased matrix metalloproteinase-2 (MMP-2), osteopontin, and interleukin-6 expression was detected in HMet + PPE rats. Furthermore, increased autophagy was detected in the HMet + PPE group. CONCLUSION: This study demonstrates that HMet may exacerbate the formation of AAA due to the increased dilation ratio partially via enhancing MMP-2 and inflammatory responses.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/induzido quimicamente , Aneurisma da Aorta Abdominal/induzido quimicamente , Glicina N-Metiltransferase/deficiência , Metionina , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/ultraestrutura , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Glicina N-Metiltransferase/sangue , Interleucina-6/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Osteopontina/metabolismo , Elastase Pancreática , Ratos Sprague-Dawley , Fatores de Risco , Fatores de Tempo
5.
PLoS One ; 14(7): e0218990, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31310631

RESUMO

Abdominal aortic aneurysm (AAA) is a life-threatening immunological disease responsible for 1 to 2% of all deaths in 65 year old or older individuals. Although mononuclear cell infiltrates have been demonstrated in AAA lesions and autoimmunity may be responsible for the initiation and account for the propagation of the disease, the information available about the pathogenesis of AAA is limited. To examine whether AAA lesions from patients with AAA contain clonally expanded α-chain TCR transcripts, we amplified by the non-palindromic adaptor-PCR (NPA-PCR)/Vα-specific PCR and/or the Vα-specific PCR these α-chain TCR transcripts. The amplified transcripts were cloned and sequenced. Substantial proportions of identical α-chain TCR transcripts were identified in AAA lesions of 4 of 5 patients, demonstrating that clonally expanded T cells are present in these AAA lesions. These results were statistically significant by the bimodal distribution. Three of 5 of these patients were typed by DNA-based HLA-typing and all three expressed DRB1 alleles containing the DRßGln70 amino acid residue that has been demonstrated to be associated with AAA. All three patients exhibited clonally expanded T cells in AAA lesions. Four of the 5 patients with AAA who exhibited clonal expansions of α-chain TCR transcripts, also exhibited clonal expansions of ß-chain TCR transcripts in AAA lesions, as we have demonstrated previously (J Immunol 192:4897, 2014). αß TCR-expressing T cells infiltrating AAA lesions contain T-cell clones which have undergone proliferation and clonal expansion in vivo in response to as yet unidentified specific antigens that may be self or nonself. These results provide additional evidence supporting the hypothesis that AAA is a specific antigen-driven T-cell autoimmune disease.


Assuntos
Antígenos/genética , Aneurisma da Aorta Abdominal/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Transcrição Genética , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos/genética , Antígenos/imunologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Células Cultivadas , Células Clonais/imunologia , Humanos , Masculino , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Análise de Sequência de RNA , Linfócitos T/imunologia , Linfócitos T/patologia
6.
Mol Cell Biochem ; 460(1-2): 29-36, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31214845

RESUMO

Cardiovascular disease (CVD) is a major cause of global mortality. The proper functioning of the endothelial layer of arteries is crucial to cardiovascular health. Retinoblastoma protein (Rb), encoded by the Rb1 gene, has been shown to offer vasoprotective effects. Herein, we investigated endothelial Rb's effects on arterial function using an endothelial-specific conditional Rb1 knockout (Rb cKO) mouse model. We found that Rb deficiency reduced dihydrofolate reductase (DHFR) activity and downstream NO production in mouse aortic endothelial cells and blocked arterial vasodilation in an endothelial DHFR-dependent manner. Rb deficiency also increased phenylephrine-triggered arterial vasoconstriction, BP levels, and pathological aortic remodeling without significantly affecting prostanoid synthesis. Employing an angiotensin II (AngII)-stimulated apolipoprotein E knockout (apoE -/-) mice fed a standard, non-atherogenic diet, Rb deficiency increased aortic diameter, stimulated abdominal aortic aneurysm (AAA) development, and reduced survival. These pathological responses to Rb deficiency in AngII-stimulated apoE-/- mice were rescued by DHFR overexpression. Cumulatively, our findings reveal that endothelial Rb positively impacts arterial function by supporting vasoprotective endothelial DHFR/NO pathway activity, leading to reduced AAA development.


Assuntos
Aneurisma da Aorta Abdominal/patologia , Células Endoteliais/metabolismo , Óxido Nítrico/metabolismo , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Tetra-Hidrofolato Desidrogenase/metabolismo , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Aneurisma da Aorta Abdominal/fisiopatologia , Artérias/metabolismo , Pressão Sanguínea , Regulação para Baixo , Células Endoteliais/patologia , Camundongos , Óxido Nítrico Sintase Tipo III/metabolismo , Prostaglandinas/metabolismo , Proteína do Retinoblastoma/deficiência , Remodelação Vascular , Vasoconstrição , Vasodilatação
8.
J Vasc Res ; 56(2): 55-64, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31085912

RESUMO

BACKGROUND: Even though hypoxia-inducible factor-1α (HIF-1α) is among the transcriptional factors demonstrated to contribute to the formation of abdominal aortic aneurysms (AAAs), the precise mechanism has been unclear. Digoxin is known as an inhibitor of HIF-1α, and shows a protective effect against the progression of AAAs. OBJECTIVES: We tested the effect of digoxin on osteoclastogenesis (OCG) and examined the pathway through which digoxin exerts inhibition of HIF-1α. MATERIALS AND METHODS: RAW 264.7 macrophage cells were cultured and stimulated by soluble receptor activator of NF-κB ligand (sRANKL) with or without digoxin. First, we tested the effect of digoxin to attenuate macrophage activation, which led to OCG, characterized by tartrate-resistant acid phosphatase (TRAP)-positive macrophages (TPMs). RESULTS: The activation of TPMs stimulated by sRANKL was attenuated by digoxin treatment. Furthermore, the receptor activator of NF-κB (RANK)/receptor activator of NF-κB ligand (RANKL) complex signaling pathway, which is stimulated by HIF-1α, was downregulated by digoxin treatment. CONCLUSIONS: These results show that digoxin attenuates OCG. By inhibition of HIF-1α, digoxin decreases OCG through the downregulation of the RANK/RANKL signaling pathway. Therefore, digoxin is a potential candidate for medical treatment of AAAs.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Digoxina/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ligante RANK/farmacologia , Animais , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Macrófagos/metabolismo , Camundongos , Osteoclastos/metabolismo , Células RAW 264.7 , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de Sinais
9.
Biomed Eng Online ; 18(1): 56, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088563

RESUMO

BACKGROUND: In clinical diagnostics, combination of different imaging techniques is applied to assess spatial configuration of the abdominal aortic aneurysm (AAA) and deformation of its wall. As deformation of aneurysm wall is crucial parameter in assessing wall rupture, we aimed to develop and validate a Non-Invasive Vision-Based System (NIVBS) for the analysis of 3D elastic artificial abdominal aortic models. 3D-printed elastic AAA models from four patients were applied for the reconstruction of real hemodynamic. During experiments, the inlet boundary conditions included the injection volume and frequency of pulsation averaged from electrocardiography traces. NIVBS system was equipped with nine cameras placed at a constant distance to record wall movement from 360o angle and a dedicated set of artificial lights providing coherent illumination. Additionally, self-prepared algorithms for image acquisition, processing, segmentation, and contour detection were used to analyze wall deformation. Finally, the shape deformation factor was applied to evaluate aorta's deformation. Experimental results were confronted with medical data from AngioCT and 2D speckle-tracking echocardiography (2DSTE). RESULTS: Image square analyses indicated that the optimal distance between the camera's lens and the investigated object was in the range of 0.30-0.35 m. There was approximately 1.44% difference observed in aneurysm diameters between NIVBS (86.57 ± 5.86 mm) and AngioCT (87.82 ± 6.04 mm) (p = 0.7764). The accuracy of developed algorithm for the reconstruction of the AAA deformation was equal to 98.56%. Bland-Altman analysis showed that the difference between clinical data (2DSTE) and predicted wall deformation (NIVBS) for all patients was 0.00 mm (confidence interval equal to 0.12 mm) for aneurysm size, 0.01 mm (confidence interval equal to 0.13 mm) and 0.00 mm (confidence interval equal to 0.09 mm) for the anterior and posterior side, as well as 0.01 mm (confidence interval equal to 0.18 mm) and 0.01 mm (confidence interval equal to 0.11 mm) for the left and right side. The optimal range of camera's lens did not affect acquired values. CONCLUSIONS: The NIVBS with proposed algorithm that reconstructs the pressure from surrounding organs is appropriate to analyze the AAAs in water environment. Moreover, NIVBS allowed detailed quantitative analysis of aneurysm sac wall deformation.


Assuntos
Aneurisma da Aorta Abdominal/patologia , Modelos Anatômicos , Algoritmos , Angiografia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Elasticidade , Humanos , Imagem Tridimensional , Impressão Tridimensional , Tomografia Computadorizada por Raios X
10.
EBioMedicine ; 43: 43-53, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30982767

RESUMO

BACKGROUND: High-density lipoproteins (HDL) are a complex mixture of lipids and proteins with vasculoprotective properties. However, HDL components could suffer post-translational modifications (PTMs) under pathological conditions, leading to dysfunctional HDL. We studied whether HDL are modified in abdominal aortic aneurysm (AAA) and the effect on HDL functionality. METHODS: HDL were isolated by ultracentrifugation from AAA tissue (HDL-T) and from plasma of healthy volunteers and then incubated with AAA tissue-conditioned medium (HDL-AAA CM). PTMs from these particles were characterized using Comet-PTM. The ability of HDL-AAA CM for promoting cholesterol efflux was determined ex vivo and in vivo by using J774A.1 [3H]cholesterol-labeled mouse macrophages and after injecting [3H]cholesterol-labeled mouse macrophages and HDL into the peritoneal cavity of wild-type C57BL/6 mice, respectively. Trp50 and Trp108 oxidized forms of APOA1 in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients and controls were measured by targeted parallel reaction monitoring. FINDINGS: Oxidation was the most prevalent PTM in apolipoproteins, particularly in APOA1. Trp50 and Trp108 in APOA1 were the residues most clearly affected by oxidation in HDL-T and in HDL-AAA CM, when compared to their controls. In addition, cholesterol efflux was decreased in macrophages incubated with HDL-AAA CM in vitro and a decreased macrophage-to-serum reverse cholesterol transport was also observed in mice injected with HDL-AAA CM. Finally, both oxidized Trp50 and Trp108 forms of APOA1 were increased in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients in relation to controls. INTERPRETATION: Oxidative modifications of HDL present in AAA tissue and plasma were closely associated with the loss of vasculoprotective properties of HDL in AAA. FUND: MINECO, ISCiii-FEDER, CIBERDEM, CIBERCV and LA CAIXA.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Apolipoproteína A-I/metabolismo , Lipoproteínas HDL/metabolismo , Oxirredução , Idoso , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/patologia , Biomarcadores , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Imuno-Histoquímica , Metabolismo dos Lipídeos , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Proteoma , Proteômica/métodos , Fatores de Risco
11.
In Vivo ; 33(3): 737-742, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31028191

RESUMO

BACKGROUND/AIM: Nine genetic loci have been associated with abdominal aortic aneurysm (AAA) susceptibility, including DAB2IP. This gene is playing a role in apoptosis, cell proliferation and epithelial-to-mesenchymal transition in cancers. This study aimed to elucidate the differential expression levels of DAB2IP in AAA tissues and investigate whether mir-363-3p and EZH2 can be considered as potential mediators of its expression. MATERIALS AND METHODS: 18 AAA samples and 15 non-aneurysmatic controls were collected. Relative mRNA expression levels of DAB2IP, EZH2 and mir-363-3p were measured using qPCR. RESULTS: DAB2IP was significant up-regulated (~2.29 fold) in AAA tissues, while EZH2 and mir-363-3p were down-regulated (3.28 and 3.62-fold, respectively). A limited negative correlation was found between the DAB2IP and EZH2 expression and between DAB2IP and the mir-363-3p. CONCLUSION: An increased expression of DAB2IP in AAA tissues was shown. We suggest 2 potential mediators of DAB2IP expression in abdominal aortic aneurysm, EZH2 and mir-363-3p.


Assuntos
Aneurisma da Aorta Abdominal/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Expressão Gênica , MicroRNAs/genética , Proteínas Ativadoras de ras GTPase/genética , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Biomarcadores , Comorbidade , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Interferência de RNA , Proteínas Ativadoras de ras GTPase/metabolismo
12.
Redox Biol ; 24: 101185, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954686

RESUMO

Hypertension and abdominal aortic aneurysm (AAA) are severe cardiovascular diseases with incompletely defined molecular mechanisms. In the current study we generated dihydrofolate reductase (DHFR) knockout mice for the first time to examine its potential contribution to the development of hypertension and AAA, as well as the underlying molecular mechanisms. Whereas the homozygote knockout mice were embryonically lethal, the heterozygote knockout mice had global reduction in DHFR protein expression and activity. Angiotensin II infusion into these animals resulted in substantially exaggerated elevation in blood pressure and development of AAA, which was accompanied by excessive eNOS uncoupling activity (featured by significantly impaired tetrahydrobiopterin and nitric oxide bioavailability), vascular remodeling (MMP2 activation, medial elastin breakdown and adventitial fibrosis) and inflammation (macrophage infiltration). Importantly, scavenging of mitochondrial reactive oxygen species with Mito-Tempo in vivo completely abrogated development of hypertension and AAA in DHFR knockout mice, indicating a novel role of mitochondria in mediating hypertension and AAA downstream of DHFR deficiency-dependent eNOS uncoupling. These data for the first time demonstrate that targeting DHFR-deficiency driven mitochondrial dysfunction may represent an innovative therapeutic option for the treatment of AAA and hypertension.


Assuntos
Anemia Megaloblástica/complicações , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/metabolismo , Hipertensão/etiologia , Hipertensão/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Tetra-Hidrofolato Desidrogenase/deficiência , Angiotensina II/metabolismo , Animais , Aneurisma da Aorta Abdominal/patologia , Pressão Sanguínea , Modelos Animais de Doenças , Loci Gênicos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Macrófagos/metabolismo , Macrófagos/patologia , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Fenótipo , Ultrassonografia
13.
Mol Med Rep ; 19(5): 3459-3468, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864718

RESUMO

Abdominal aortic aneurysm (AAA) is an asymptomatic, potentially lethal disease whose ruptures have a high mortality rate. An effective pharmacological approach to decrease expansion or prevent the rupture of AAAs in humans remains lacking. Previous studies have suggested that activator protein 1 (c­Jun/AP­1) and C/EBP homologous protein (Chop) are involved in the development of AAA. The purpose of the present study was to investigate whether c­Jun/AP­1 mediates Chop overexpression in AAA. c­Jun/AP­1 and Chop protein levels were determined in an angiotensin II (Ang II)­induced AAA model using apolipoprotein E­deficient mice. Additionally, mouse aortic smooth muscle cells (MOVAS cell line) were treated with Ang II. Apoptosis was evaluated via TUNEL assay, MOVAS cell migration ability was assessed by monolayer wound healing assay and the levels of c­Jun/AP­1 and Chop were determined by western blotting, immunofluorescence and immunocytochemical assays. Following c­Jun silencing using c­Jun­specific small interfering (si)RNA, Chop expression was evaluated. Furthermore, chromatin immunoprecipitation (ChIP) was used to investigate whether c­Jun/Ap­1 binds directly to the DNA damage­inducible transcript 3 protein (Ddit3) promoter. It was observed that c­Jun/AP­1 and Chop were synchronously overexpressed in Ang II­induced AAA and Ang II­treated cells, and that apoptosis and migration were induced by Ang II. In addition, Chop was suppressed when c­Jun was silenced by targeted siRNA. Notably, the ChIP assay demonstrated that the DNA fragments pulled down by primary antibodies against c­Jun/Ap­1 were able to be amplified by (Ddit3) promoter­specific primers. c­Jun/AP­1 may therefore mediate Chop expression in MOVAS cells via Ddit3. These results suggested that c­Jun/AP­1 may be a novel target for AAA therapy.


Assuntos
Angiotensina II/efeitos adversos , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição CHOP/genética , Angiotensina II/metabolismo , Animais , Aneurisma da Aorta Abdominal/patologia , Células Cultivadas , Modelos Animais de Doenças , Inativação Gênica , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas , Ligação Proteica , RNA Interferente Pequeno/genética , Fator de Transcrição CHOP/metabolismo
14.
Eur J Pharmacol ; 853: 145-152, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30898623

RESUMO

As the most common form of aortic aneurysm, abdominal aortic aneurysm (AAA) is associated with the proliferation and apoptosis of vascular smooth muscle cells (VSMCs). Our present study found that during H2O2 or NaAsO2 induced injury of VSMC, the expression of miR-155-5p significantly increased. While silencing of miR-155-5p can attenuate H2O2 or NaAsO2 suppressed viability and induced apoptosis of VSMCs. In silico analysis and western blot analysis suggested that miR-155-5p can suppress the expression of FOS and ZIC3 in VSMCs by targeting their 3'UTR. Over expression of FOS or ZIC3 can abolish H2O2 treatment and miR-155-5p induced suppression of VSMC viability. The inhibitor of NF-κB (p65), while not STAT3, can abolish H2O2 induced expression of miR-155-5p and cell apoptosis. In addition, H2O2 treatment can increase the phosphorylation and nuclear translocation of p65 in VSMCs. The expression of miR-155-5p in cells isolated from participants diagnosed with AAA were significantly greater than that in the normal group. Further, miR-155-5p was negative correlated with the expression of FOS and ZIC3 in cells from AAA patients. Collectively, miR-155-5p can regulate the viability and apoptosis of VSMCs to trigger the progression of AAA. It might be an effective therapeutic target for the treatment of AAA in clinical practice.


Assuntos
Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Sobrevivência Celular/genética , Proteínas de Homeodomínio/genética , MicroRNAs/genética , Músculo Liso Vascular/patologia , Proteínas Proto-Oncogênicas c-fos/genética , Fatores de Transcrição/genética , Apoptose/genética , Progressão da Doença , Regulação da Expressão Gênica/genética , Humanos , Fator de Transcrição RelA/metabolismo
15.
Life Sci ; 224: 51-57, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30905780

RESUMO

The pathogenesis of abdominal aortic aneurysm remains unclear. The aim of the present study was to establish whether isoleucyl-tRNA synthetase (Iars) regulates the differentiation and apoptosis of vascular smooth muscle cells (VSMCs) during the development of abdominal aortic aneurysm (AAA). In addition, the contribution of various signaling pathways towards this process was ascertained. The study demonstrated that the expression of Iars, p-p38, osteopontin (OPN) and Bcl-2-associated X protein (Bax) clearly increased, while levels of p-PI3K and smooth muscle 22 alpha (SM22α) decreased significantly in AAA tissues. Inhibition of Iars significantly reduced the incidence of angiotensin II (AngII)-induced AAA in mice, coincident with decreased activity of the p38 MAPK pathway and increased PI3K pathway activity. AngII-induced phenotypic switching and apoptosis of VSMCs decreased following the inhibition of Iars in vitro. Upregulation of the IARS gene induced phenotypic switching and apoptosis in VSMCs in addition to increased p38 MAPK pathway activation and reduced PI3K pathway activation. Following pretreatment with an activator of the PI3K pathway, expression of Iars and the phenotypic markers of VSMCs were not affected, while apoptosis of VSMCs decreased. Similarly, inhibition of the p38 MAPK pathway in VSMCs did not affect the expression of Iars or the degree of cell apoptosis, but reduced phenotypic switching was observed. Conclusively, upregulation of Iars regulates the phenotypic switching and apoptosis of VSMCs. Targeting Iars may be a promising strategy to prevent abdominal aortic aneurysm.


Assuntos
Aneurisma da Aorta Abdominal/patologia , Apoptose , Regulação da Expressão Gênica , Isoleucina-tRNA Ligase/metabolismo , Músculo Liso Vascular/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Aneurisma da Aorta Abdominal/metabolismo , Proliferação de Células , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Transdução de Sinais
16.
Circ Cardiovasc Imaging ; 12(3): e008707, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30871334

RESUMO

BACKGROUND: Molecular magnetic resonance imaging is a promising modality for the characterization of abdominal aortic aneurysms (AAAs). The combination of different molecular imaging biomarkers may improve the assessment of the risk of rupture. This study investigates the feasibility of imaging inflammatory activity and extracellular matrix degradation by concurrent dual-probe molecular magnetic resonance imaging in an AAA mouse model. METHODS: Osmotic minipumps with a continuous infusion of Ang II (angiotensin II; 1000 ng/[kg·min]) to induce AAAs were implanted in apolipoprotein-deficient mice (N=58). Animals were assigned to 2 groups. In group 1 (longitudinal group, n=13), imaging was performed once after 1 week with a clinical dose of a macrophage-specific iron oxide-based probe (ferumoxytol, 4 mgFe/kg, surrogate marker for inflammatory activity) and an elastin-specific gadolinium-based probe (0.2 mmol/kg, surrogate marker for extracellular matrix degradation). Animals were then monitored with death as end point. In group 2 (week-by-week-group), imaging with both probes was performed after 1, 2, 3, and 4 weeks (n=9 per group). Both probes were evaluated in 1 magnetic resonance session. RESULTS: The combined assessment of inflammatory activity and extracellular matrix degradation was the strongest predictor of AAA rupture (sensitivity 100%; specificity 89%; area under the curve, 0.99). Information from each single probe alone resulted in lower predictive accuracy. In vivo measurements for the elastin- and iron oxide-probe were in good agreement with ex vivo histopathology (Prussian blue-stain: R2=0.96, P<0.001; Elastica van Giesson stain: R2=0.79, P<0.001). Contrast-to-noise ratio measurements for the iron oxide and elastin-probe were in good agreement with inductively coupled mass spectroscopy ( R2=0.88, R2=0.75, P<0.001) and laser ablation coupled to inductively coupled plasma-mass spectrometry. CONCLUSIONS: This study demonstrates the potential of the concurrent assessment of inflammatory activity and extracellular matrix degradation by dual-probe molecular magnetic resonance imaging in an AAA mouse model. Based on the combined information from both molecular probes, the rupture of AAAs could reliably be predicted.


Assuntos
Aorta Abdominal/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Elastina/metabolismo , Matriz Extracelular/metabolismo , Óxido Ferroso-Férrico/administração & dosagem , Gadolínio DTPA/administração & dosagem , Mediadores da Inflamação/metabolismo , Imagem por Ressonância Magnética , Imagem Molecular/métodos , Angiotensina II , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/patologia , Estudos de Viabilidade , Gadolínio DTPA/análogos & derivados , Masculino , Camundongos Knockout para ApoE , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Tempo
17.
Mol Cells ; 42(3): 218-227, 2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30726659

RESUMO

This study was designed to determine the effects of the long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) on vascular smooth muscle cell (VSMC) apoptosis and extracellular matrix (ECM) disruption in a murine abdominal aortic aneurysm (AAA) model. After injection of PVT1-silencing lentiviruses, AAA was induced in Apolipoprotein E-deficient (ApoE-/-) male mice by angiotensin II (Ang II) infusion for four weeks. After Ang II infusion, mouse serum levels of pro-inflammatory cytokines were analysed, and aortic tissues were isolated for histological, RNA, and protein analysis. Our results also showed that PVT1 expression was significantly upregulated in abdominal aortic tissues from AAA patients compared with that in controls. Additionally, Ang II treatment significantly increased PVT1 expression, both in cultured mouse VSMCs and in AAA murine abdominal aortic tissues. Of note, the effects of Ang II in facilitating cell apoptosis, increasing matrix metalloproteinase (MMP)-2 and MMP-9, reducing tissue inhibitor of MMP (TIMP)-1, and promoting switching from the contractile to synthetic phenotype in cultured VSMCs were enhanced by overexpression of PVT1 but attenuated by knockdown of PVT1. Furthermore, knockdown of PVT1 reversed Ang II-induced AAA-associated alterations in mice, as evidenced by attenuation of aortic diameter dilation, marked adventitial thickening, loss of elastin in the aorta, enhanced aortic cell apoptosis, elevated MMP-2 and MMP-9, reduced TIMP-1, and increased pro-inflammatory cytokines. In conclusion, our findings demonstrate that knockdown of lncRNA PVT1 suppresses VSMC apoptosis, ECM disruption, and serum pro-inflammatory cytokines in a murine Ang II-induced AAA model.


Assuntos
Aneurisma da Aorta Abdominal/genética , Apoptose , Matriz Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , RNA Longo não Codificante/genética , Idoso , Idoso de 80 Anos ou mais , Angiotensina II/farmacologia , Animais , Aneurisma da Aorta Abdominal/patologia , Apolipoproteínas E/deficiência , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Inflamação/patologia , Camundongos , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/metabolismo
18.
Ann Vasc Surg ; 58: 381.e5-381.e9, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30731218

RESUMO

Neoplasias affecting the aorta are usually due to a variety of thoracic and abdominal tumors, which are more common than primary tumors of the aortic wall. Those tumors that can invade the abdominal aorta are usually sarcomas, which are able to mimic, both clinically and radiologically, an aortic disease such as an aneurysm or a dissection. There are few clinical scenarios where surgical resection and aortic repair needs to be performed, and indications have not still been clearly established in the literature. We describe the case of a patient with a periaortic lymphoma who presented an aortic rupture and was successfully treated with an urgent endovascular repair.


Assuntos
Falso Aneurisma/etiologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/etiologia , Ruptura Aórtica/etiologia , Linfoma Difuso de Grandes Células B/patologia , Idoso , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/patologia , Falso Aneurisma/cirurgia , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/cirurgia , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/patologia , Ruptura Aórtica/cirurgia , Aortografia/métodos , Implante de Prótese Vascular , Angiografia por Tomografia Computadorizada , Procedimentos Endovasculares , Humanos , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/terapia , Masculino , Invasividade Neoplásica , Recidiva , Resultado do Tratamento
19.
J Vasc Surg ; 70(2): 588-598.e2, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30792060

RESUMO

OBJECTIVE: Macrophages play a critical role in the initiation and progression of abdominal aortic aneurysm (AAA) and are classically distinguished into M1 "proinflammatory" and M2 "anti-inflammatory" macrophages. Topical application of elastase associated with transforming growth factor ß (TGF-ß) systemic neutralization reproduces the main pathologic features of human AAA, offering a new model to investigate their role. The aim of this study was to investigate whether macrophages contribute to the expression of canonical M1/M2 markers in the aorta in the AAA model induced by elastase and systemic blockade of TGF-ß and whether blocking of TGF-ß activity affects macrophage phenotype and the expression of the M2 marker arginase 1 (ARG1). METHODS: C57Bl/6J male mice (6-8 weeks old) were randomly assigned to three experimental groups: mice that had local application of heat-inactivated elastase or elastase and mice that had elastase application and received injection of anti-TGF-ß (elastase + anti-TGF-ß group). Monocyte-macrophage depletion was achieved in the elastase + anti-TGF-ß group using liposome clodronate. Macrophage phenotype was characterized by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. Human infrarenal AAA tissues (n = 10) were obtained to analyze ARG1 expression. RESULTS: Analysis of gene expression in the infrarenal aortic wall revealed that after 14 days, no significant difference for the expression of CCL2, NOS2, and Ym1/2 was observed in the elastase group compared with the elastase + anti-TGF-ß group, whereas the expression of ARG1, interleukin (IL) 1ß, and IL-6 was significantly increased. Macrophage depletion in the elastase + anti-TGF-ß group led to a significant decrease of IL-1ß, IL-6, ARG1, and Ym1/2 gene expression. Immunofluorescent staining confirmed that TGF-ß neutralization significantly enhanced ARG1 protein expression in the aneurysmal tissue. Flow cytometry analysis revealed an increase of macrophages expressing ARG1 in the aorta of mice treated with elastase + anti-TGF-ß compared with the elastase group, and their proportion increased with aneurysmal dilation. In humans, ARG1 protein expression was increased in aneurysmal tissues compared with controls, and positive cells were mainly found in the adventitia. CONCLUSIONS: TGF-ß neutralization finely tunes macrophage phenotype in elastase-induced AAA and leads to an increase in ARG1 gene and protein expression in the aortic wall. Even if further studies are required to elucidate its role in AAA development, ARG1 could represent a new prognostic or therapeutic target in aneurysmal disease.


Assuntos
Anticorpos Neutralizantes , Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/enzimologia , Arginase/metabolismo , Macrófagos/enzimologia , Elastase Pancreática , Fator de Crescimento Transformador beta/metabolismo , Animais , Aorta Abdominal/imunologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Fenótipo , Transdução de Sinais , Fator de Crescimento Transformador beta/imunologia , Regulação para Cima
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA