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2017 ; 8
(47
): 82049-82063
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Ionising radiation increases permeability of endothelium through ADAM10-mediated
cleavage of VE-cadherin
#MMPMID29137243
Kabacik S
; Raj K
Oncotarget
2017[Oct]; 8
(47
): 82049-82063
PMID29137243
show ga
The association between ionising radiation (IR) exposure and risk of
cardiovascular diseases (CVD) is well documented, but the underlying mechanism is
still poorly understood. As atherosclerotic plaques are the most common cause of
CVD, we investigated the effects of IR on one of the critical parameters for
atherosclerotic plaque formation - endothelium permeability to macromolecules. We
used endothelial cells from human coronary artery as a model of the endothelial
layer. Our results show that exposure of this endothelial layer to IR increased
its permeability to macromolecules of various sizes in a dose-dependent manner.
Immunofluorescence analysis revealed disruption of cell junctions caused by
decreased amounts of two junction proteins, one of which is vascular endothelial
cadherin (VE-cadherin). The reduction in the level of this protein was not due to
diminished transcription but to protein processing instead. We observed a
radiation dose-dependent increase in the cleavage of VE-cadherin by ADAM10. This
was not mediated through the canonical VEGF route but was instead accompanied by
intra-cellular calcium release. Importantly, inhibition of ADAM10 activity
rescued IR-induced permeability. Our observations demonstrate that exposure to IR
activates ADAM10 to cleave VE-cadherin leading to augmented endothelium
permeability; a feature that can lead to the development of atherosclerotic
plaques and increase the risk of cardiovascular disease.