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Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial
adherens junction integrity and barrier function
#MMPMID28319894
Chattopadhyay R
; Raghavan S
; Rao GN
Redox Biol
2017[Aug]; 12
(?): 438-455
PMID28319894
show ga
Resolvins are a novel class of lipid mediators that play an important role in the
resolution of inflammation, although the underlying mechanisms are not very
clear. To explore the anti-inflammatory mechanisms of resolvins, we have studied
the effects of resolvin D1 (RvD1) on lipopolysaccharide (LPS)-induced endothelial
barrier disruption as it is linked to propagation of inflammation. We found that
LPS induces endothelial cell (EC) barrier disruption via xanthine oxidase
(XO)-mediated reactive oxygen species (ROS) production, protein tyrosine
phosphatase SHP2 inactivation and Fyn-related kinase (Frk) activation leading to
tyrosine phosphorylation of ?-catenin and VE-cadherin and their dissociation from
each other affecting adherens junction (AJ) integrity and thereby increasing
endothelial barrier permeability. RvD1 attenuated LPS-induced AJ disassembly and
endothelial barrier permeability by arresting tyrosine phosphorylation of
?-catenin and VE-cadherin and their dislocation from AJ via blockade of
XO-mediated ROS production and thereby suppression of SHP2 inhibition and Frk
activation. We have also found that the protective effects of RvD1 on EC barrier
function involve ALX/FPR2 and GPR32 as inhibition or neutralization of these
receptors negates its protective effects. LPS also increased XO activity, SHP2
cysteine oxidation and its inactivation, Frk activation, ?-catenin and
VE-cadherin tyrosine phosphorylation and their dissociation from each other
leading to AJ disruption with increased vascular permeability in mice arteries
and RvD1 blocked all these effects. Thus, RvD1 protects endothelial AJ and its
barrier function from disruption by inflammatory mediators such as LPS via a
mechanism involving the suppression of XO-mediated ROS production and blocking
SHP2 inactivation.
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