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1.
PLoS Biol ; 17(6): e3000313, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31185010

RESUMO

Blood-brain barrier (BBB) defects and cerebrovascular dysfunction contribute to amyloid-ß (Aß) brain accumulation and drive Alzheimer disease (AD) pathology. By regulating vascular functions and inflammation in the microvasculature, a disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) plays a significant protective effect in atherosclerosis and stroke. However, whether ADAMTS13 influences AD pathogenesis remains unclear. Using in vivo multiphoton microscopy, histological, behavioral, and biological methods, we determined BBB integrity, cerebrovascular dysfunction, amyloid accumulation, and cognitive impairment in APPPS1 mice lacking ADAMTS13. We also tested the impact of viral-mediated expression of ADAMTS13 on cerebrovascular function and AD-like pathology in APPPS1 mice. We show that ADAMTS13 deficiency led to an early and progressive BBB breakdown as well as reductions in vessel density, capillary perfusion, and cerebral blood flow in APPPS1 mice. We found that deficiency of ADAMTS13 increased brain plaque load and Aß levels and accelerated cerebral amyloid angiopathy (CAA) by impeding BBB-mediated clearance of brain Aß, resulting in worse cognitive decline in APPPS1 mice. Virus-mediated expression of ADAMTS13 attenuated BBB disruption and increased microvessels, capillary perfusion, and cerebral blood flow in APPPS1 mice already showing BBB damage and plaque deposition. These beneficial vascular effects were reflected by increase in clearance of cerebral Aß, reductions in Aß brain accumulation, and improvements in cognitive performance. Our results show that ADAMTS13 deficiency contributes to AD cerebrovascular dysfunction and the resulting pathogenesis and cognitive deficits and suggest that ADAMTS13 may offer novel therapeutic opportunities for AD.


Assuntos
Proteína ADAMTS13/metabolismo , Proteína ADAMTS13/fisiologia , Circulação Cerebrovascular/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiologia , Encéfalo/metabolismo , Disfunção Cognitiva , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
2.
Transfusion ; 58(10): 2453-2462, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30208220

RESUMO

ADAMTS13 is an enzyme that acts by cleaving prothrombotic von Willebrand factor (VWF) multimers from the vasculature in a highly regulated manner. In pathologic states such as thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies (TMAs), VWF can bind to the endothelium and form large multimers. As the anchored VWF chains grow, they provide a greater surface area to bind circulating platelets (PLTs), generating unique thrombi that characterize TTP. This results in microvasculature thrombosis, obstruction of blood flow, and ultimately end-organ damage. Initial presentations of TTP usually occur in an acute manner, typically developing due to an autoimmune response toward, or less commonly a congenital deficiency of, ADAMTS13. Triggers for TMAs that can be associated with ADAMTS13 deficiency, including TTP, have been linked to events that place a burden on hemostatic regulation, such as major trauma and pregnancy. The treatment plan for cases of suspected TTP consists of emergent therapeutic plasma exchange that is continued on a daily basis until normalization of PLT counts. However, a subset of these patients does not respond favorably to standard therapies. These patients necessitate a better understanding of their diseases for the advancement of future therapeutic options. Given ADAMTS13's key role in the cleavage of VWF and the prevention of PLT-rich thrombi within the microvasculature, future treatments may include anti-VWF therapeutics, recombinant ADAMTS13 infusions, and ADAMTS13 expression via gene therapy.


Assuntos
Proteína ADAMTS13/fisiologia , Microangiopatias Trombóticas/etiologia , Proteína ADAMTS13/deficiência , Feminino , Humanos , Troca Plasmática , Gravidez , Terapêutica/métodos , Microangiopatias Trombóticas/terapia , Fator de von Willebrand/metabolismo
3.
Thromb Haemost ; 118(4): 758-767, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29618156

RESUMO

BACKGROUND: Endovascular treatment improves outcome in patients with acute ischaemic stroke due to large vessel occlusion in general. But outcome in some of these patients is jeopardized by recanalization failure or bleeding. OBJECTIVES: This study aimed to determine a possible association of mediators of inflammation and haemostasis (C-reactive protein, interleukin-6, matrix metalloproteinase-9, monocyte chemoattractant protein-1, asymmetric dimethylarginine [ADMA], symmetric dimethylarginine, von Willebrand factor and a disintegrin and metalloproteinase with a thrombospondin type 1 motif 13 [ADAMTS-13]) with the post-intervention grade of reperfusion, complications and clinical outcome in patients who underwent endovascular treatment of ischaemic stroke. PATIENTS/METHODS: Forty-one patients with acute ischaemic stroke due to large vessel occlusion were prospectively enrolled into the study. Peripheral venous blood was taken prior to treatment and 24 hours and 3, 7 and 90 days after symptom onset. The post-intervention grade of reperfusion was determined using the modified Treatment in Cerebral Infarction (mTICI) score. Clinical outcome on day 90 was assessed using the modified Rankin's scale (mRS). RESULTS: Low ADAMTS-13 activity (p = 0.009) and missing of statin therapy (p = 0.038) on admission were independently associated with unfavourable outcome (mRS: 5-6). Patients with unsuccessful reperfusion (mTICI: 0-1) showed higher ADMA levels on admission (p = 0.018). However, this association could not be confirmed in the binary logistic regression analysis. CONCLUSION: Low ADAMTS-13 activity is a predictor of unfavourable outcome in patients with ischaemic stroke undergoing endovascular therapy. Further studies are warranted to elucidate the clinical and potential therapeutic role of ADAMTS-13 in acute ischaemic stroke.


Assuntos
Proteína ADAMTS13/sangue , Isquemia Encefálica/tratamento farmacológico , Procedimentos Endovasculares/métodos , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Proteína ADAMTS13/fisiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Hemostasia , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Traumatismo por Reperfusão , Reprodutibilidade dos Testes , Resultado do Tratamento
4.
Indian J Gastroenterol ; 36(5): 380-389, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28980147

RESUMO

BACKGROUND: Non-cirrhotic intrahepatic portal hypertension (NCIPH) is characterized by thrombotic microangiopathy of the portal venous system, low ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs-13), and high vWF (von Willebrand factor) levels. This study aimed to screen for ADAMTS13 mutations, focusing on the CUB domain, in these patients. METHODS: Prospectively recruited NCIPH patients and healthy volunteers underwent tests for plasma vWF-ADAMTS13 balance. Sanger sequencing of the CUB domain of ADAMTS13 was done in a subset of the NCIPH patients, and the detected mutation was screened for in all the study participants. Next-generation sequencing of clinically relevant exome and liver immunostaining for ADAMTS13 was done in patients with detected ADAMTS13 mutation. RESULTS: Plasma vWF-ADAMTS13 balance was significantly altered in 24 NCIPH patients (Child's class A:23, B:1) as compared to 22 controls. On initial sequencing of the CUB domain (17 cases and 3 controls), one NCIPH patient showed a rare missense variant (SNV) at position c.3829C >T resulting in p.R1277W (rs14045669). Subsequent RFLP analysis targeted to the R1277W variant did not detect this in any other NCIPH patient, nor in any of the 22 controls. The NCIPH patient with the R1277W variant had severe ADAMTS13 deficiency, consistently high vWF, other missense SNVs in ADAMTS13, vWF, and complement genes. Immunostaining of his liver biopsy revealed globules of ADAMTS13 within stellate cells. CONCLUSIONS: We report missense variants in ADAMTS13, vWF, and complement genes in a patient with NCIPH who had decreased secretion and activity of ADAMTS13 protein. Further studies are needed in NCIPH patients in this regard.


Assuntos
Proteína ADAMTS13/genética , Proteína ADAMTS13/metabolismo , Estudos de Associação Genética , Hipertensão Portal/genética , Hipertensão Portal/fisiopatologia , Mutação de Sentido Incorreto/genética , Proteína ADAMTS13/fisiologia , Adolescente , Adulto , Idoso , Estudos de Coortes , Proteínas do Sistema Complemento/genética , Feminino , Humanos , Hipertensão Portal/metabolismo , Masculino , Pessoa de Meia-Idade , Selectina-P/sangue , Estudos Prospectivos , Adulto Jovem , Fator de von Willebrand/genética
5.
Nephrology (Carlton) ; 22(11): 913-920, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27507004

RESUMO

AIM: The ADAMTS13-von Willebrand factor (vWF) axis has been suggested to play a critical role in the pathophysiology of ischaemia-reperfusion injury (IRI) in the heart or brain. Therefore, we aimed to investigate whether this axis was involved in the pathophysiology of IRI-induced acute kidney injury. METHODS: We performed renal IRI in ADAMTS13 knockout (KO) or wild type (WT) mice. Functional and histological kidney damage, and inflammation were compared and the effect of anti-vWF antibodies in ADAMTS13 KO mice was assessed. RESULTS: Following IRI, the blood and kidney ADAMTS13 levels were significantly decreased. vWF expression was significantly upregulated in both the medulla and cortex of injured kidneys as shown by immunohistochemistry and western blot analyses. There was also an increased level of vWF dimers after IRI. In ADAMTS13 KO mice, kidney vWF levels were further increased and this was associated with greater endothelial and epithelial injury compared to WT mice, suggesting an important role of vWF in renal IRI. In addition, the number of Gr-1+ neutrophils was significantly higher in the kidneys of ADAMTS13 KO mice compared to WT mice, whereas F4/80 macrophage numbers were unchanged. In ADAMTS13 KO mice, administration of anti-vWF antibodies after IRI partially reversed renal injury. CONCLUSION: Our data show that the ADAMTS13-vWF axis is partially involved in the pathophysiology of kidney IRI, suggesting that regulating ADAMTS13- and vWF-dependent mechanisms could have therapeutic potential to limit renal IRI.


Assuntos
Proteína ADAMTS13/fisiologia , Rim/irrigação sanguínea , Traumatismo por Reperfusão/etiologia , Fator de von Willebrand/fisiologia , Proteína ADAMTS13/análise , Lesão Renal Aguda/etiologia , Animais , Inflamação/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de von Willebrand/análise
6.
Int J Hematol ; 104(5): 534-539, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27696191

RESUMO

ADAMTS13, a plasma reprolysin-like metalloprotease, proteolyzes von Willebrand factor (VWF). ADAMTS13 is primarily synthesized by hepatic stellate cells (HSCs), and mainly regulates thrombogenesis by cleaving VWF. Recent studies demonstrate that ADAMTS13 also plays a role in the down-regulation of inflammation, regulation angiogenesis, and degradation of extracellular matrix. The purpose of this review is to introduce the state of progress with respect to some of the theorized roles of ADAMTS13.


Assuntos
Proteína ADAMTS13/fisiologia , Matriz Extracelular/metabolismo , Humanos , Inflamação/metabolismo , Neovascularização Fisiológica , Trombose/metabolismo , Trombose/prevenção & controle
7.
Am J Kidney Dis ; 68(5): 726-732, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27497525

RESUMO

BACKGROUND: Altered levels of von Willebrand factor (vWF) and ADAMTS13 can promote thrombosis and disturb blood flow in kidney microcirculations. We investigated the association of serum vWF:ADAMTS13 ratio in relation to decline in kidney function. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,479 individuals (mean age, 65.1±5.9 [SD] years; 43% men) from the population-based Rotterdam Study. PREDICTORS: vWF, ADAMTS13, and vWF:ADAMTS13 ratio. OUTCOMES & MEASUREMENTS: Annual decline in estimated glomerular filtration rate (eGFR), halving of eGFR, and new-onset eGFR<60mL/min/1.73m2 were assessed. RESULTS: During a median follow-up of 11 (range, 7.81-13.57) years, 500 cases of new-onset eGFR<60mL/min/1.73m2 occurred. The population had a mean eGFR decline of 0.96±0.92mL/min/1.73m2 per year. Higher vWF:ADAMTS13 ratio was associated with steeper annual decline in eGFR (difference, -0.06 [95% CI, -0.09 to -0.02] mL/min/1.73m2 per year) and higher risk for new-onset eGFR<60mL/min/1.73m2 (OR, 1.13; 95% CI, 1.01-1.27). Likewise, higher vWF:ADAMTS13 ratio was associated with higher risk for halving of eGFR (OR, 1.40; 95% CI, 1.02-1.93). After adjustment for cardiovascular risk factors and blood group, effect estimates remained the same. LIMITATIONS: No data available for albuminuria. Participants were classified based on a single measurement of vWF and ADAMTS13. CONCLUSIONS: In this population-based study, we showed that higher vWF:ADAMTS13 ratio is associated with decline in kidney function, suggesting a role of elevated prothrombotic factors in the development and progression of kidney disease.


Assuntos
Proteína ADAMTS13/sangue , Proteína ADAMTS13/fisiologia , Rim/fisiopatologia , Fator de von Willebrand/análise , Idoso , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
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