Nur77 limits endothelial barrier disruption to LPS in the mouse lung.
Am J Physiol Lung Cell Mol Physiol
; 317(5): L615-L624, 2019 11 01.
Article
em En
| MEDLINE
| ID: mdl-31461311
ABSTRACT
Nur77 is an orphan nuclear receptor implicated in the regulation of a wide range of biological processes, including the maintenance of systemic blood vessel homeostasis. Although Nur77 is known to be expressed in the lung, its role in regulating pulmonary vascular functions remains entirely unknown. In this study, we found that Nur77 is expressed at high levels in the lung, and its expression is markedly upregulated in response to LPS administration. While the pulmonary vasculature of mice that lacked Nur77 appeared to function normally under homeostatic conditions, we observed a dramatic decrease in its barrier functions after exposure to LPS, as demonstrated by an increase in serum proteins in the bronchoalveolar lavage fluid and a reduction in the expression of endothelial junctional proteins, such as vascular endothelial cadherin (VE-cadherin) and ß-catenin. Similarly, we found that siRNA knockdown of Nur77 in lung microvascular endothelial cells also reduced VE-cadherin and ß-catenin expression and increased the quantity of fluorescein isothiocyanate-labeled dextran transporting across LPS-injured endothelial monolayers. Consistent with Nur77 playing a vascular protective role, we found that adenoviral-mediated overexpression of Nur77 both enhanced expression of VE-cadherin and ß-catenin and augmented endothelial barrier protection to LPS in cultured cells. Mechanistically, Nur77 appeared to mediate its protective effects, at least in part, by binding to ß-catenin and preventing its degradation. Our findings demonstrate a key role for Nur77 in the maintenance of lung endothelial barrier protection to LPS and suggest that therapeutic strategies aimed at augmenting Nur77 levels might be effective in treating a wide variety of inflammatory vascular diseases of the lung.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pneumonia
/
Permeabilidade Capilar
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Lipopolissacarídeos
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Células Endoteliais
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Lesão Pulmonar Aguda
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Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article