Hyaluronic Acid binding protein 2 is a novel regulator of vascular integrity.
Arterioscler Thromb Vasc Biol
; 30(3): 483-90, 2010 Mar.
Article
em En
| MEDLINE
| ID: mdl-20042707
ABSTRACT
OBJECTIVE:
The disruption of the endothelial cell barrier is a critical feature of inflammation and an important contributing factor to acute lung injury (ALI), an inflammatory condition that is a major cause of morbidity and mortality in critically ill patients. We evaluated the role of the extracellular serine protease, hyaluronic acid binding protein 2 (HABP2), in vascular barrier regulation. METHODS ANDRESULTS:
By using immunoblot and immunohistochemical analysis, we observed that lipopolysaccharide (LPS) induces HABP2 expression in murine lung endothelium in vivo and in human pulmonary microvascular endothelial cells (ECs) in vitro. High-molecular-weight hyaluronan (HMW-HA, approximately 1x10(6) Da) decreased HABP2 protein expression in human pulmonary microvascular ECs and decreased purified HABP2 enzymatic activity, whereas low-molecular-weight HA (LMW-HA, approximately 2500 Da) increased these activities. The effects of LMW-HA, but not HMW-HA, on HABP2 activity were inhibited with a peptide of the polyanion-binding domain of HABP2. Silencing (small interfering RNA) HABP2 expression augmented HMW-HA-induced EC barrier enhancement and inhibited LPS and LMW-HA-mediated EC barrier disruption, results that were reversed with overexpression of HABP2. Silencing protease-activated receptor 1 and 3, RhoA, or Rho kinase expression attenuated LPS-, LMW-HA-, and HABP2-mediated EC barrier disruption. By using murine models of acute lung injury, we observed that LPS- and ventilator-induced pulmonary vascular hyperpermeability was significantly reduced with vascular silencing (small interfering RNA) of HABP2.CONCLUSIONS:
HABP2 negatively regulates vascular integrity via activation of protease-activated receptor/RhoA/Rho kinase signaling and represents a potentially useful therapeutic target for syndromes of increased vascular permeability.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Endotélio Vascular
/
Serina Endopeptidases
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Permeabilidade da Membrana Celular
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Lesão Pulmonar Aguda
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
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Humans
/
Male
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article