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1.
Angiology ; 71(1): 62-69, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31088126

RESUMO

The prevalence of coronary intimal thickening (IT) was assessed in fetuses and pediatric population. We studied the coronary arteries of 63 hearts obtained from fetuses, infants, children, and adolescents, deceased from noncardiac disease or trauma. Histomorphometric analysis, planimetry, and immunohistochemical studies were conducted. Intimal thickening consisted of proliferation of smooth muscle cells and scarce monocytes embedded in amorphous deposits within the internal elastic membrane (IEM). Intermingled lesions of intimal hyperplasia and parietal nonstenotic plaques were also observed. Intimal thickening was found in 10% of 20 fetuses, in 33.3% of 18 infants, 73.3% of 15 children, and 100% of 10 adolescents. A significant correlation (r = 0.671, P < 0.001) was found between the extent of IT and age. The IEM was duplicated or interrupted in 43% of patients, showing a positive correlation with the degree of IT (P = 0.01). Intimal thickening was predominantly found near bifurcation sites in the left anterior descending coronary artery (55.6%) and in zones free of bifurcation in the right coronary artery (75%). In conclusion, the prevalence and extension of IT lesions are higher at older ages within a young population. Intimal thickening may be regarded as the first event occurring in coronary preatherosclerosis, preceding lipid deposition.


Assuntos
Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Coração Fetal/patologia , Neointima , Placa Aterosclerótica , Túnica Íntima/patologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Progressão da Doença , Feminino , Idade Gestacional , Humanos , Hiperplasia , Lactente , Recém-Nascido , Masculino
2.
EBioMedicine ; 46: 274-289, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31395500

RESUMO

BACKGROUND: Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12; TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Tnfrsf12a; Fn14) participate in the inflammatory response associated with vascular remodeling. However, the functional effect of TWEAK on vascular smooth muscle cells (VSMCs) is not completely elucidated. METHODS: Next generation sequencing-based methods were performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwell migration assays were used to analyze VSMCs proliferation and migration. Mouse wire injury model was done to evaluate the role of TWEAK/Fn14 during neointimal hyperplasia. FINDINGS: TWEAK up-regulated 1611 and down-regulated 1091 genes in VSMCs. Using a gene-set enrichment method, we found a functional module involved in cell proliferation defined as the minimal network connecting top TWEAK up-regulated genes. In vitro experiments in wild-type or Tnfrsf12a deficient VSMCs demonstrated that TWEAK increased cell proliferation, VSMCs motility and migration. Mechanistically, TWEAK increased cyclins (cyclinD1), cyclin-dependent kinases (CDK4, CDK6) and decreased cyclin-dependent kinase inhibitors (p15lNK4B) mRNA and protein expression. Downregulation of p15INK4B induced by TWEAK was mediated by mitogen-activated protein kinase ERK and Akt activation. Tnfrsf12a or Tnfsf12 genetic depletion and pharmacological intervention with TWEAK blocking antibody reduced neointimal formation, decreasing cell proliferation, cyclin D1 and CDK4/6 expression, and increasing p15INK4B expression compared with wild type or IgG-treated mice in wire-injured femoral arteries. Finally, immunohistochemistry in human coronary arteries with stenosis or in-stent restenosis revealed high levels of Fn14, TWEAK and PCNA in VSMCs enriched areas of the neointima as compared with healthy coronary arteries. INTERPRETATION: Our data define a major role of TWEAK/Fn14 in the control of VSMCs proliferation and migration during neointimal hyperplasia after wire injury in mice, and identify TWEAK/Fn14 as a potential target for treating in-stent restenosis. FUND: ISCiii-FEDER, CIBERCV and CIBERDEM.


Assuntos
Angioplastia/efeitos adversos , Reestenose Coronária/etiologia , Reestenose Coronária/metabolismo , Citocina TWEAK/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor de TWEAK/metabolismo , Animais , Biomarcadores , Movimento Celular , Proliferação de Células , Reestenose Coronária/patologia , Modelos Animais de Doenças , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Modelos Biológicos , Miócitos de Músculo Liso/metabolismo , Complicações Pós-Operatórias , Túnica Íntima/metabolismo , Túnica Íntima/patologia
3.
Forensic Sci Med Pathol ; 15(4): 591-594, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446611

RESUMO

The body of a 43-year-old African woman with a history of aortic aneurysm and hypertension was forensically investigated after her sudden death. The cause of death was related to a cardiac tamponade due to a ruptured aneurysm of the ascending aorta. Post-mortem gross examination showed an abnormal whitish discoloration of the intima with fibrous thickening of the aortic wall. Several arteries (left main and circumflex coronaries, carotid, renal and iliac arteries) showed similar features. Upon histological examination, the aortic aneurysm as well as the other arteries sampled showed mucoid degeneration, excess mucopolysaccharides and pools of mucin inside the intima and the media associated with collagen and elastic fiber destruction and loss of smooth muscle cells. This pattern strongly suggested the diagnosis of intimomedial mucoid degeneration (IMMD), a rare arterial disorder consisting of a progressive deposition of mucin into the intima and media, with a strong prevalence in middle-aged black African females with high blood pressure. In addition to the typical features of IMMD, histological examination of the ascending aorta showed a thickening of the adventita with sparse mixed inflammatory infiltrates and fibrosis, suggesting an additional chronic infectious aortitis. No infectious agent was detected. The body of literature on IMMD is reviewed and the origin of death is discussed in this case report.


Assuntos
Aorta/patologia , Aneurisma Aórtico/patologia , Glicosaminoglicanos/metabolismo , Mucinas/metabolismo , Túnica Íntima/patologia , Túnica Média/patologia , Adulto , Túnica Adventícia/patologia , Grupo com Ancestrais do Continente Africano , Vasos Coronários/patologia , Morte Súbita/etiologia , Feminino , Fibrose/patologia , Patologia Legal , Humanos , Hipertensão/complicações , Túnica Íntima/metabolismo , Túnica Média/metabolismo
4.
J Forensic Sci ; 64(6): 1916-1920, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31150105

RESUMO

Atrial septal defects (ASDs) are one of the most prevalent congenital cardiac anomalies in adults. These interatrial communications can produce changes in the right heart (remodeling and failure) and the lungs (pulmonary hypertension). Most adults with ASDs are surgically treated with excellent results. However, a small fraction of patients is at risk for postoperative complications, particularly the persistence of pulmonary hypertension. A case of a 47-year-old woman who was found unresponsive in the bathroom of her house and died despite resuscitative efforts is described. According to medical records, the woman underwent a surgical repair of an atrial septal defect at the age of 37. At the autopsy, macroscopic and microscopic signs of advanced pulmonary hypertension were detected, highlighting the importance for the forensic pathologists to recognize pulmonary hypertension as a cause of sudden death in adults with a history of late surgical closure of an atrial septal defect.


Assuntos
Morte Súbita/etiologia , Comunicação Interatrial/cirurgia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Feminino , Comunicação Interatrial/complicações , Humanos , Hipertrofia Ventricular Direita/patologia , Pulmão/patologia , Pessoa de Meia-Idade , Miocárdio/patologia , Tamanho do Órgão , Placa Aterosclerótica/patologia , Artéria Pulmonar/patologia , Túnica Íntima/patologia
5.
J Forensic Leg Med ; 66: 79-85, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31229802

RESUMO

Although the diagnosis of drowning may appear straightforward the reality is that it is sometimes one of the most difficult in forensic pathology. To begin with, there is no universal agreement on what constitutes drowning with some definitions using the term in the absence of a lethal outcome. Next are the significant problems that arise in finding immersed bodies and in assessing the death scene. Prolonged post mortem intervals are associated with artefactual modifications of the body from putrefaction and post mortem animal predation. Both of these may create and disguise injuries. The absence of pathognomonic pathological features at autopsy and the presence of potentially life threatening underlying organic illnesses complicate determination of both the cause and manner of death. There may even be no autopsy findings to indicate that immersion had occurred. Finally, the unreliability of laboratory tests with significant overlap with control cases where death had no association with immersion presents further problems. Thus lethal drowning remains a complex event that requires the use of a wide variety of information sources, not just data gleaned from the dissection table.


Assuntos
Afogamento/diagnóstico , Patologia Legal/métodos , Animais , Aorta/patologia , Comorbidade , Consenso , Diatomáceas/isolamento & purificação , Afogamento/patologia , Eletrólitos/análise , Hemorragia/patologia , Humanos , Pulmão/patologia , Tamanho do Órgão , Seios Paranasais/patologia , Mudanças Depois da Morte , Sistema Respiratório/patologia , Pele/patologia , Baço/patologia , Terminologia como Assunto , Tomografia Computadorizada por Raios X , Túnica Íntima/patologia
6.
J Med Case Rep ; 13(1): 189, 2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31227015

RESUMO

BACKGROUND: Vasculopathy in systemic lupus erythematosus is a rare form of vascular involvement characterized by non-inflammatory vascular injury with the accumulation of immune complexes in the walls of the arteries, resulting in luminal narrowing. While previous reports have demonstrated vasculitis in the large vessels or vasculopathy in the small vessels, vasculopathy in large vessels has not yet been reported. CASE PRESENTATION: We present the case of a 43-year-old Japanese woman with peripheral large vessel vasculopathy associated with systemic lupus erythematosus. She presented a 7-year history of progressive headaches and intermittent claudication, although she had no atherosclerotic risk factors. Vascular ultrasonography and enhanced computed tomography showed multiple vascular stenoses and occlusion. The histological findings of her left temporal artery revealed narrowing of the lumen caused by intimal thickening without inflammatory cells and the deposition of immunoglobulin G, complement component 3, and fibrinogen in the wall of the intima. Beraprost and cilostazol improved arterial occlusion without immunosuppressive therapy. CONCLUSIONS: Large vessel vasculopathy should be considered another potential cause of arterial stenoses and occlusion in patients with lupus when they have peripheral arterial disease despite having no atherosclerotic risk factors.


Assuntos
Arteriopatias Oclusivas/patologia , Lúpus Eritematoso Sistêmico/complicações , Artérias Temporais/patologia , Túnica Íntima/patologia , Adulto , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/etiologia , Complemento C3/metabolismo , Feminino , Fibrinogênio/metabolismo , Humanos , Imunoglobulina G/metabolismo , Artérias Temporais/diagnóstico por imagem , Artérias da Tíbia/diagnóstico por imagem , Túnica Íntima/metabolismo
7.
World Neurosurg ; 122: e577-e583, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31108073

RESUMO

BACKGROUND: Flow diverter stents have become a useful tool for treatment of complex intracranial aneurysms. A serious complication is incomplete wall apposition after flow diverter placement. The aim of this study was to present a comprehensive investigation of hemodynamic changes induced by incomplete expansion of a flow diverter. METHODS: A case of a patient treated for an internal carotid artery aneurysm by flow diversion with incomplete wall apposition was virtually investigated. The effect of incomplete flow diverter expansion was studied using image-based blood flow simulations under physiologically relevant flow conditions based on patient-specific clinical data. RESULTS: The numerical results revealed that incomplete expansion at the proximal end of the stent had minimal impact on the intra-aneurysmal blood flow alteration. A region of nonphysiologically high wall shear stress was observed near the contact area between the incompletely expanded proximal end of the flow diverter and the parent artery, which caused an intimal hyperplasia in this region. These simulation results were consistent with the real-life clinical course and outcome. CONCLUSIONS: The results of this study can be considered during treatment planning of complex cases where the risk of incomplete flow diverter expansion exists. Further studies are required before results can also be used to support the decision process about antiplatelet therapy and additional interventions to improve wall apposition.


Assuntos
Doenças das Artérias Carótidas/terapia , Embolização Terapêutica/efeitos adversos , Aneurisma Intracraniano/terapia , Túnica Íntima/patologia , Velocidade do Fluxo Sanguíneo/fisiologia , Prótese Vascular/efeitos adversos , Doenças das Artérias Carótidas/fisiopatologia , Artéria Carótida Interna , Embolização Terapêutica/instrumentação , Hemodinâmica/fisiologia , Humanos , Hiperplasia/etiologia , Hiperplasia/fisiopatologia , Aneurisma Intracraniano/fisiopatologia , Pessoa de Meia-Idade , Modelos Biológicos , Stents/efeitos adversos , Telas Cirúrgicas
8.
Phytomedicine ; 58: 152754, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31009837

RESUMO

BACKGROUND: Salvianolic acid B (Sal B), a water-soluble compound extracted from Salvia miltiorrhiza that has been widely used to treat cardiovascular diseases for hundreds of years in China, exerts cardiovascular protection by multiple mechanisms. miR-146a is involved in vascular smooth muscle cell (VSMC) phenotypic modulation and proliferation. However, it has yet to be investigated whether the cardiovascular protective effect of Sal B is mediated by miR-146a. PURPOSE: To determine the relationship among the cardiovascular protective effect of Sal B, miR-146a expression, and VSMC proliferation. METHODS: MTS assay and cell counting were performed to evaluate the effect of Ang II, Sal B and miR-146a on VSMC proliferation. The neointima hyperplasia was assessed by hematoxylin/eosin staining. qRT-PCR was used to detect the expression of miR-146a, KLF5, cyclin D1 and PCNA. Western blot analysis was used to detect the expressions of KLF5, cyclin D1 and PCNA after miR-20b-5p was knocked down or overexpressed in VSMC. RESULTS: Sal B suppressed intimal hyperplasia induced by carotid artery ligation and decreased Ang II-induced VSMC proliferation by down-regulating the positive cell-cycle regulators KLF5 and cyclin D1. Further experiments showed that VSMC proliferation and upregulation of KLF5 and cyclin D1 induced by Ang II were accompanied by elevated miR-146a level. Furthermore, overexpression of miR-146a promoted and knockdown of miR-146a reduced Ang II-induced VSMC proliferation and ameliorated intimal hyperplasia induced by carotid artery ligation. Sal B inhibited Ang II-induced VSMC proliferation by suppressing miR-146a expression. CONCLUSION: Sal B inhibited Ang II-induced VSMC proliferation in vitro and intimal hyperplasia in vivo by downregulating miR-146a expression.


Assuntos
Benzofuranos/farmacologia , Artérias Carótidas/patologia , MicroRNAs/genética , Músculo Liso Vascular/efeitos dos fármacos , Túnica Íntima/patologia , Angiotensina II/farmacologia , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/cirurgia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperplasia/tratamento farmacológico , Hiperplasia/genética , Hiperplasia/patologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Neointima/tratamento farmacológico , Neointima/genética , Neointima/patologia , Túnica Íntima/efeitos dos fármacos
9.
Vasc Endovascular Surg ; 53(5): 379-386, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982448

RESUMO

INTRODUCTION: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid-polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. METHODS: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy-intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the -intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. RESULTS: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. CONCLUSIONS: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Artéria Carótida Primitiva/efeitos dos fármacos , Portadores de Fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Neointima , Polímeros/química , Sinvastatina/administração & dosagem , Túnica Íntima/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Administração Oral , Animais , Caproatos/química , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Artéria Carótida Primitiva/metabolismo , Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/fisiopatologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Composição de Medicamentos , Humanos , Ácido Hialurônico/química , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Lactonas/química , Micelas , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ratos Sprague-Dawley , Ácidos Siálicos/química , Sinvastatina/química , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Túnica Íntima/fisiopatologia
10.
Cardiovasc Pathol ; 40: 68-71, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30928813

RESUMO

Enterocolic lymphocytic phlebitis (ELP) is a rare enteropathy characterized by lymphocytic phlebitis of the mesenteric veins without arteritis. Idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare disease similar to ELP, characterized by myointimal hyperplasia that constricts the lumen of veins, causing mucosal injury. A 62-year-old man with chief complaint of abdominal pain was treated by partial resection of the ileum after 3 months of conservative therapy. The pathologic diagnosis was ELP with prominent myointimal hyperplasia. Histologically, the lesion consisted of lymphocytic infiltration into the vein accompanied by prominent myointimal hyperplasia and perivenous concentric fibrosis, which are characteristics shared by ELP and IMHMV. The observations in this case suggest that some of ELP and IMHMV may belong to the same disease spectrum. Furthermore, perivascular concentric fibrosis was a remarkable observation that may contribute to differential diagnosis between ELP and "true" IMHMV.


Assuntos
Linfócitos T CD4-Positivos/patologia , Enteropatias/patologia , Veias Mesentéricas/patologia , Flebite/patologia , Túnica Íntima/patologia , Biópsia , Angiografia por Tomografia Computadorizada , Diagnóstico Diferencial , Fibrose , Humanos , Hiperplasia , Imuno-Histoquímica , Enteropatias/diagnóstico por imagem , Enteropatias/cirurgia , Masculino , Veias Mesentéricas/diagnóstico por imagem , Veias Mesentéricas/cirurgia , Pessoa de Meia-Idade , Flebite/diagnóstico por imagem , Flebite/cirurgia , Flebografia/métodos , Valor Preditivo dos Testes , Resultado do Tratamento , Túnica Íntima/diagnóstico por imagem , Túnica Íntima/cirurgia
11.
G Ital Nefrol ; 36(2)2019 Apr.
Artigo em Italiano | MEDLINE | ID: mdl-30983175

RESUMO

Native arteriovenous fistula is the preferred vascular access because of it does not usually cause infections and seems to be closely related with prolonged patient survival, compared to prosthetic grafts and central venous catheters; it also is cost effective. Venous stenosis is one of the main causes of AVF failure. It is caused by a number of upstream and downstream events. The former group comprises hemodynamic and surgical stressors, inflammatory stimuli and uraemia, while downstream events involve the proliferation of smooth muscle cells and myofibroblasts and the development of neo-intimal hyperplasia. Percutaneous transluminal angioplasty is the gold standard for arteriovenous fistula stenosis. It allows the visualization of the whole vascular circuit and the immediate use of the vascular access for the next dialysis session. Ultrasound-guided percutaneous endovascular angioplasty is a feasible and safe alternative to conventional fluoroscopic technique: it is equally effective in treating arteriovenous fistula stenosis, but it presents the advantage of not using contrast media or ionizing radiation. The aim of this review is to report the latest evidence on cellular and molecular mechanisms that contribute to the development of neo-intimal hyperplasia, as well as the current and future therapeutic perspectives, especially concerning the use of anti-proliferative drugs, and the efficacy of the ultrasound-guided angioplasty in restoring and maintaining the vascular access patency over time.


Assuntos
Angioplastia/métodos , Fístula Arteriovenosa/terapia , Ultrassonografia de Intervenção , Angioplastia com Balão/métodos , Constrição Patológica/terapia , Stents Farmacológicos , Humanos , Hiperplasia/etiologia , Miócitos de Músculo Liso/patologia , Complicações Pós-Operatórias/terapia , Diálise Renal/efeitos adversos , Stents , Túnica Íntima/patologia
12.
Eur J Pharmacol ; 854: 213-223, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30940448

RESUMO

Vascular smooth muscle cell (VSMC) proliferation and migration are crucial events in the pathological course of atherosclerosis and restenosis after percutaneous coronary intervention (PCI). Dioscin has been shown to exhibit powerful cardiovascular protective effects and potent therapeutic potential in cancer owing to the inhibition of cell proliferation and migration. However, its effects on arterial wall hypertrophy-related diseases caused by VSMC proliferation and migration remain unclear. In this study, we investigated the effects of dioscin on intimal hyperplasia after balloon injury in vivo, its effects on VSMC proliferation and migration in vitro, and the mechanisms underlying these effects. Results showed that dioscin treatment significantly inhibited VSMC proliferation and intimal thickening after balloon injury. In cultured VSMCs, treatment with dioscin significantly decreased fetal bovine serum or platelet-derived growth factor-induced cell proliferation and migration. Moreover, dioscin inhibited the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and expression of Forkhead box M1 (FoxM1) and its downstream target genes. FoxM1 knockdown with shRNA partially counteracted the inhibitory effects of dioscin on cell proliferation and migration. In conclusion, we demonstrated that dioscin attenuated neointima formation in response to balloon injury by suppressing VSMC proliferation and migration through MAPK-FoxM1 pathway. Our data suggested that dioscin might be a potential therapeutic agent for atherosclerosis and restenosis after PCI.


Assuntos
Lesões das Artérias Carótidas/patologia , Diosgenina/análogos & derivados , Proteína Forkhead Box M1/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia , Animais , Lesões das Artérias Carótidas/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Hiperplasia/tratamento farmacológico , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/patologia , Fenótipo , Ratos , Ratos Sprague-Dawley
13.
PLoS One ; 14(3): e0214654, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30925179

RESUMO

Pulmonary intimal sarcoma (PIS) constitutes a rare sarcoma originating from the intimal cells of pulmonary arteries. The pathogenesis of PIS remains to be elucidated and specific treatments have not been established; therefore, prognosis is generally poor. The purpose of our study was to isolate and characterize PIS cells from a specimen resected from a patient with PIS. The surgical specimen was minced and incubated, and spindle-shaped and small cells were successfully isolated and designated as PIS-1. PIS-1 cells at passages 8-9 were used for all in vitro and in vivo experiments. Immunocytochemistry showed that PIS-1 cells were positive for vimentin, murine double minute 2, and CD44 and negative for α-smooth muscle actin, CD31, von Willebrand factor, and desmin. PIS-1 cells exhibited the hallmarks of malignant cells including the potential for autonomous proliferation, anchorage-independent growth, invasion, genetic instability, and tumorigenicity in severe combined immunodeficiency mice. The PIS-1 cells highly expressed tyrosine kinase receptors such as platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2. Pazopanib, a multi-targeted tyrosine kinase inhibitor, suppressed the proliferation of PIS-1 cells in vitro and the growth of tumors formed from xenografted PIS-1 cells. A PIS cell line was thus successfully established. The PIS-1 cells highly expressed tyrosine kinase receptors, which may be a target for treatment of PIS.


Assuntos
Artéria Pulmonar/patologia , Sarcoma/patologia , Sarcoma/cirurgia , Túnica Íntima/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Masculino , Camundongos , Invasividade Neoplásica , Receptores Proteína Tirosina Quinases/metabolismo , Sarcoma/genética , Sarcoma/metabolismo
14.
J Forensic Sci ; 64(5): 1555-1558, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30893469

RESUMO

Syphilis, a sexually transmitted infection caused by the bacterium Treponema palladium, is experiencing a worldwide resurgence. The risk of syphilis infection is particularly high in men who have sex with men (MSM), especially those who are human immunodeficiency virus (HIV)-positive. Untreated syphilis can lead to rare but severe late-stage complications, including syphilitic aortitis. Herein, we present an autopsy case of a ruptured thoracic aneurysm that resulted from an undetected case of syphilitic aortitis in an HIV-positive Japanese MSM with undiagnosed syphilis. Although no syphilitic skin lesions were observed on the body, anatomical changes consistent with a syphilitic etiology were present at the site of the rupture, including medial aortic scarring with "tree-bark"-like atherosclerotic plaque. In addition, heart blood was positive for T. palladium in a latex agglutination test. This case highlights for forensic pathologists the importance of recognizing syphilis as a possible underlying cause of sudden death among HIV-positive MSM.


Assuntos
Aneurisma Roto/microbiologia , Morte Súbita/etiologia , Infecções por HIV/complicações , Sífilis Cardiovascular/diagnóstico , Aneurisma Roto/patologia , Coinfecção , Fibrose/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Túnica Íntima/microbiologia , Túnica Íntima/patologia
15.
Nat Rev Cardiol ; 16(7): 389-406, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846875

RESUMO

Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima in which the balance of pro-inflammatory and inflammation-resolving mechanisms dictates the final clinical outcome. Intimal infiltration and modification of plasma-derived lipoproteins and their uptake mainly by macrophages, with ensuing formation of lipid-filled foam cells, initiate atherosclerotic lesion formation, and deficient efferocytotic removal of apoptotic cells and foam cells sustains lesion progression. Defective efferocytosis, as a sign of inadequate inflammation resolution, leads to accumulation of secondarily necrotic macrophages and foam cells and the formation of an advanced lesion with a necrotic lipid core, indicative of plaque vulnerability. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules. One of the major effects of inflammation resolution mediators is phenotypic conversion of pro-inflammatory macrophages into macrophages that suppress inflammation and promote healing. In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids (in particular leukotrienes) is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions. In this Review, we discuss the mechanisms of the formation of clinically dangerous atherosclerotic lesions and the potential of pro-resolving mediator therapy to inhibit this process.


Assuntos
Aterosclerose/etiologia , Aterosclerose/fisiopatologia , Inflamação/etiologia , Inflamação/fisiopatologia , Macrófagos/fisiologia , Túnica Íntima/patologia , Animais , Apoptose , Aterosclerose/prevenção & controle , Humanos , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Metabolismo dos Lipídeos , Lipoproteínas/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais
16.
Diabetes Care ; 42(5): 980-982, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30862652

RESUMO

OBJECTIVE: This study was conducted to determine the relationship between dysglycemia and the coronary artery vasa vasorum density. RESEARCH DESIGN AND METHODS: The left anterior descending coronary artery was removed from 57 deceased individuals during autopsy, and the capillaries in the vessel wall were identified using fluorescent immunohistochemical staining. HbA1c was determined in postmortem whole blood for each individual. The density of the vasa vasorum in the intima-media and the adventitia was manually quantified and recorded by readers unaware of the individual's other characteristics. RESULTS: The individuals with diabetes had a lower density of the coronary vasa vasorum than those without diabetes. The higher the HbA1c, the lower the density of these vessels in the adventitia and entire vessel wall. CONCLUSIONS: Dysglycemia-induced damage to the vasa vasorum may promote ischemic heart disease in people with diabetes.


Assuntos
Vasos Coronários/patologia , Transtornos do Metabolismo de Glucose/patologia , Vasa Vasorum/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Autopsia , Glicemia/metabolismo , Contagem de Células , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Feminino , Transtornos do Metabolismo de Glucose/sangue , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/sangue , Isquemia Miocárdica/patologia , Túnica Íntima/patologia
17.
Int J Mol Sci ; 20(4)2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30791562

RESUMO

Over eighty million people in the United States have cardiovascular disease that can affect the heart causing myocardial infarction; the carotid arteries causing stroke; and the lower extremities leading to amputation. The treatment for end-stage cardiovascular disease is surgical-either endovascular therapy with balloons and stents-or open reconstruction to reestablish blood flow. All interventions damage or destroy the protective inner lining of the blood vessel-the endothelium. An intact endothelium is essential to provide a protective; antithrombotic lining of a blood vessel. Currently; there are no agents used in the clinical setting that promote reendothelialization. This process requires migration of endothelial cells to the denuded vessel; proliferation of endothelial cells on the denuded vessel surface; and the reconstitution of the tight adherence junctions responsible for the formation of an impermeable surface. These processes are all regulated in part and are dependent on small GTPases. As important as the small GTPases are for reendothelialization, dysregulation of these molecules can result in various vascular pathologies including aneurysm formation, atherosclerosis, diabetes, angiogenesis, and hypertension. A better understanding of the role of small GTPases in endothelial cell migration is essential to the development for novel agents to treat vascular disease.


Assuntos
Proteínas Monoméricas de Ligação ao GTP/metabolismo , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo , Animais , Biomarcadores , Movimento Celular , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Humanos , Proteínas Monoméricas de Ligação ao GTP/genética , Família Multigênica , Substrato Quinase C Rico em Alanina Miristoilada/genética , Substrato Quinase C Rico em Alanina Miristoilada/metabolismo , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Doenças Vasculares/patologia
18.
Forensic Sci Med Pathol ; 15(2): 252-257, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30810977

RESUMO

Coronary arteritis is an uncommon cause of sudden death in non-atherosclerotic coronary diseases, and is mostly associated with systemic vasculitis or systemic autoimmune diseases; therefore, sudden death due to isolated coronary arteritis rarely occurs. The case described in this report is that of a 34-year-old man with no significant personal medical history who died suddenly after presenting with nausea. Postmortem examination revealed a significant infiltration of lymphocytes predominantly on the adventitia and periadventitial tissues of the coronary arteries in the epicardium. The lymphocytic infiltrate partially extended to the thickened intima with fibrosis, destructing the media and internal elastic lamina, and the lumen was occluded by a thrombus in the left main stem and left anterior descending branch. The arterial walls exhibited focal fibrinoid necrosis with regression in the intima and fibrous scars with angiogenesis in the media and adventitia. Focal myocardial infarction was detected in the left ventricle as a fibrotic change of the myocardium. No findings associated with vasculitis were discerned in the aorta, other peripheral arteries, or major organs. Laboratory tests of postmortem blood samples returned negative results for antinuclear antibodies, cryoglobulin, immunoglobulin G4, and cytoplasmic anti-neutrophil cytoplasmic antibodies for myeloperoxidase and proteinase 3. These autopsy findings suggest that the sudden death was caused by isolated necrotizing vasculitis that is assumed to be polyarteritis nodosa localized at the coronary arteries. However, pathological characteristics may not be exactly the same between isolated necrotizing vasculitis in the coronary arteries and polyarteritis nodosa.


Assuntos
Trombose Coronária/patologia , Vasos Coronários/patologia , Morte Súbita Cardíaca/etiologia , Poliarterite Nodosa/patologia , Adulto , Humanos , Linfócitos/patologia , Masculino , Infarto do Miocárdio/patologia , Túnica Íntima/patologia , Túnica Média/patologia
19.
Genes (Basel) ; 10(1)2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30669689

RESUMO

BACKGROUND: CD34⁺ Endothelial Progenitor Cells (EPCs) play an important role in the recovery of injured endothelium and contribute to atherosclerosis (ATH) pathogenesis. Previously we described a potential atherogenic role for miR-125 that we aimed to confirm in this work. METHODS: Microarray hybridization, TaqMan Low Density Array (TLDA) cards, qPCR, and immunohistochemistry (IHC) were used to analyze expression of the miRNAs, proteins and transcripts here studied. RESULTS: Here we have demonstrated an increase of resident CD34-positive cells in the aortic tissue of human and mice during ATH progression, as well as the presence of clusters of CD34-positive cells in the intima and adventitia of human ATH aortas. We introduce miR-351, which share the seed sequence with miR-125, as a potential effector of CD34. We show a splicing event at an internal/cryptic splice site at exon 8 of the murine Cd34 gene (exonic-switch) that would regulate the differential accession of miRNAs (including miR-125) to the coding region or to the 3'UTR of Cd34. CONCLUSIONS: We introduce new potential mediators of ATH progression (CD34 cell-clusters, miR-351), and propose a new mechanism of miRNA action, linked to a cryptic splicing site in the target-host gene, that would regulate the differential accession of miRNAs to their cognate binding sites.


Assuntos
Antígenos CD34/genética , Aterosclerose/genética , MicroRNAs/genética , Sítios de Splice de RNA , Processamento Alternativo , Animais , Antígenos CD34/metabolismo , Aorta/metabolismo , Aorta/patologia , Aterosclerose/patologia , Éxons , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Túnica Íntima/metabolismo , Túnica Íntima/patologia
20.
Arterioscler Thromb Vasc Biol ; 39(3): 387-401, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30651003

RESUMO

Objective- Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member of several coronary artery disease-associated pathways. Thus, our objective is to determine the role of FURIN in atherosclerosis. Approach and Results- In vitro, FURIN inhibitor treatment resulted in reduced monocyte migration and reduced macrophage and vascular endothelial cell inflammatory and cytokine gene expression. In vivo, administration of an irreversible inhibitor of FURIN, α-1-PDX (α1-antitrypsin Portland), to hyperlipidemic Ldlr-/- mice resulted in lower atherosclerotic lesion area and a specific reduction in severe lesions. Significantly lower lesional macrophage and collagen area, as well as systemic inflammatory markers, were observed. MMP2 (matrix metallopeptidase 2), an effector of endothelial function and atherosclerotic lesion progression, and a FURIN substrate was significantly reduced in the aorta of inhibitor-treated mice. To determine FURIN's role in vascular endothelial function, we administered α-1-PDX to Apoe-/- mice harboring a wire injury in the common carotid artery. We observed significantly decreased carotid intimal thickness and lower plaque cellularity, smooth muscle cell, macrophage, and inflammatory marker content, suggesting protection against vascular remodeling. Overexpression of FURIN in this model resulted in a significant 67% increase in intimal plaque thickness, confirming that FURIN levels directly correlate with atherosclerosis. Conclusions- We show that systemic inhibition of FURIN in mice decreases vascular remodeling and atherosclerosis. FURIN-mediated modulation of MMP2 activity may contribute to the atheroprotection observed in these mice.


Assuntos
Aterosclerose/prevenção & controle , Furina/antagonistas & inibidores , Placa Aterosclerótica/tratamento farmacológico , alfa 1-Antitripsina/uso terapêutico , Animais , Aorta/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Artéria Carótida Primitiva , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Indução Enzimática/efeitos dos fármacos , Furina/genética , Furina/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Metaloproteinase 2 da Matriz/análise , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/fisiologia , Placa Aterosclerótica/patologia , Receptores de LDL/deficiência , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia , Remodelação Vascular , alfa 1-Antitripsina/farmacologia
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