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

Autor: Somasundaram Raghavan, Rima Chattopadhyay, Gadiparthi N. Rao
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Lipopolysaccharides
WT
wild type
AJ
adherens junctions
Clinical Biochemistry
Vascular permeability
Protein Tyrosine Phosphatase
Non-Receptor Type 11
Protein tyrosine phosphatase
TER
transendothelial electrical resistance
Biochemistry
15-LOX
15-lipoxygenase
CSN
cysteine sulfonate
WB
Western blotting
chemistry.chemical_compound
Mice
0302 clinical medicine
Adherens junctions
lcsh:QH301-705.5
Barrier function
lcsh:R5-920
PTK
protein tyrosine kinase
IP
immunoprecipitation
Endothelial barrier function
ROS
TJ
tight junctions
3. Good health
Cell biology
GPR32
Endothelial stem cell
lcsh:Medicine (General)
PTP
protein tyrosine phosphatase
Signal Transduction
Research Paper
Xanthine Oxidase
Docosahexaenoic Acids
Down-Regulation
Protective Agents
Resolvin D1
Adherens junction
03 medical and health sciences
ROS
reactive oxygen species
EV
Evans blue
Human Umbilical Vein Endothelial Cells
HUVEC
human umbilical vein endothelial cells
Animals
Humans
LSGS
low-serum growth supplements
VE-cadherin
vascular endothelial cadherin
Inflammation
XO
xanthine oxidase
Organic Chemistry
Endothelial Cells
Tyrosine phosphorylation
Lipid signaling
DHA
docosahexanoic acid
Frk
Fyn-related kinase
GJ
gap junctions
030104 developmental biology
chemistry
lcsh:Biology (General)
CD
chow diet
SHP2
Reactive Oxygen Species
RvD1
Resolvin D1
030217 neurology & neurosurgery
Zdroj: Redox Biology, Vol 12, Iss, Pp 438-455 (2017)
Redox Biology
ISSN: 2213-2317
Popis: 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.
Graphical abstract fx1
Highlights • RvD1 protects EC barrier function from LPS-induced disruption by inhibition of Frk-mediated ⍺-catenin dissociation from VE-cadherin. • RvD1 inhibits LPS-induced Frk activation via suppression of XO-mediated ROS production and prevention of SHP2 inactivation. • Both ALX/FPR2 and GPR32 are involved in the protective effects of RvD1 on endothelial AJ integrity and barrier function.
Databáze: OpenAIRE
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