Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function

Rima Chattopadhyay, Somasundaram Raghavan, Rao Gadiparthi

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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 α-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 α-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, α-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.

Original languageEnglish (US)
Pages (from-to)438-455
Number of pages18
JournalRedox Biology
Volume12
DOIs
StatePublished - Aug 1 2017

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Adherens Junctions
Xanthine Oxidase
Lipopolysaccharides
Reactive Oxygen Species
Catenins
Phosphorylation
Tyrosine
Phosphotransferases
Chemical activation
Endothelial cells
Permeability
Endothelial Cells
Inflammation
Protein Tyrosine Phosphatases
Capillary Permeability
Cysteine
Anti-Inflammatory Agents
Arteries
resolvin D1
Lipids

All Science Journal Classification (ASJC) codes

  • Organic Chemistry
  • Clinical Biochemistry

Cite this

Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function. / Chattopadhyay, Rima; Raghavan, Somasundaram; Gadiparthi, Rao.

In: Redox Biology, Vol. 12, 01.08.2017, p. 438-455.

Research output: Contribution to journalArticle

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