Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function
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)...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-08-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231717300642 |
| _version_ | 1818294739416383488 |
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| author | Rima Chattopadhyay Somasundaram Raghavan Gadiparthi N. Rao |
| author_facet | Rima Chattopadhyay Somasundaram Raghavan Gadiparthi N. Rao |
| author_sort | Rima Chattopadhyay |
| collection | DOAJ |
| description | 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. Keywords: Resolvin D1, Endothelial barrier function, Adherens junctions, ROS, SHP2, Inflammation |
| first_indexed | 2024-12-13T03:36:32Z |
| format | Article |
| id | doaj.art-6323aac08e3b4834a814bf1512fec487 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-13T03:36:32Z |
| publishDate | 2017-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-6323aac08e3b4834a814bf1512fec4872022-12-22T00:01:02ZengElsevierRedox Biology2213-23172017-08-0112438455Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier functionRima Chattopadhyay0Somasundaram Raghavan1Gadiparthi N. Rao2Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USACorrespondence to: Department of Physiology, University of Tennessee HSC, 71 S. Manassas Street, Memphis, TN 38163, USA.; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USAResolvins 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. Keywords: Resolvin D1, Endothelial barrier function, Adherens junctions, ROS, SHP2, Inflammationhttp://www.sciencedirect.com/science/article/pii/S2213231717300642 |
| spellingShingle | Rima Chattopadhyay Somasundaram Raghavan Gadiparthi N. Rao Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function Redox Biology |
| title | Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function |
| title_full | Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function |
| title_fullStr | Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function |
| title_full_unstemmed | Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function |
| title_short | Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function |
| title_sort | resolvin d1 via prevention of ros mediated shp2 inactivation protects endothelial adherens junction integrity and barrier function |
| url | http://www.sciencedirect.com/science/article/pii/S2213231717300642 |
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