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Cardiovasc Res. 2015 Jul 1;107(1):131-42. doi: 10.1093/cvr/cvv142. Epub 2015 May 6.

Isthmin is a novel vascular permeability inducer that functions through cell-surface GRP78-mediated Src activation.

Author information

1
Department of Biological Sciences, Faculty of Science, 14 Science Drive 4, National University of Singapore, Singapore, Singapore 117543.
2
Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore Immunology Program, Life Science Institute, National University of Singapore, Singapore, Singapore 117456.
3
Department of Biological Sciences, Faculty of Science, 14 Science Drive 4, National University of Singapore, Singapore, Singapore 117543 dbsgerw@nus.edu.sg.

Abstract

AIMS:

Isthmin (ISM) is a recently identified 60 kDa secreted angiogenesis inhibitor. Two cell-surface receptors for ISM have been defined, the high-affinity glucose-regulated protein 78 kDa (GRP78) and the low-affinity αvβ5 integrin. As αvβ5 integrin plays an important role in pulmonary vascular permeability (VP) and ISM is highly expressed in mouse lung, we sought to clarify the role of ISM in VP.

METHODS AND RESULTS:

Recombinant ISM (rISM) dose-dependently enhances endothelial monolayer permeability in vitro and local dermal VP when administered intradermally in mice. Systemic rISM administration through intravenous injection leads to profound lung vascular hyperpermeability but not in other organs. Mechanistic investigations using molecular, biochemical approaches and specific chemical inhibitors revealed that ISM-GRP78 interaction triggers a direct interaction between GRP78 and Src, leading to Src activation and subsequent phosphorylation of adherens junction proteins and loss of junctional proteins from inter-endothelial junctions, resulting in enhanced VP. Dynamic studies of Src activation, VP and apoptosis revealed that ISM induces VP directly via Src activation while apoptosis contributes indirectly only after prolonged treatment. Furthermore, ISM is significantly up-regulated in lipopolysaccharide (LPS)-treated mouse lung. Blocking cell-surface GRP78 by systemic infusion of anti-GRP78 antibody significantly attenuates pulmonary vascular hyperpermeability in LPS-induced acute lung injury (ALI) in mice.

CONCLUSION:

ISM is a novel VP inducer that functions through cell-surface GRP78-mediated Src activation as well as induction of apoptosis. It induces a direct GRP78-Src interaction, leading to cytoplasmic Src activation. ISM contributes to pulmonary vascular hyperpermeability of LPS-induced ALI in mice.

KEYWORDS:

Acute lung injury; GRP78; Isthmin; Src; Vascular permeability

PMID:
25952901
DOI:
10.1093/cvr/cvv142
[Indexed for MEDLINE]

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