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2017 ; 2017
(ä): 6893560
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AM966, an Antagonist of Lysophosphatidic Acid Receptor 1, Increases Lung
Microvascular Endothelial Permeability through Activation of Rho Signaling
Pathway and Phosphorylation of VE-Cadherin
#MMPMID28348461
Cai J
; Wei J
; Li S
; Suber T
; Zhao J
Mediators Inflamm
2017[]; 2017
(ä): 6893560
PMID28348461
show ga
Maintenance of pulmonary endothelial barrier integrity is important for reducing
severity of lung injury. Lysophosphatidic acid (LPA) regulates cell motility,
cytoskeletal rearrangement, and cell growth. Knockdown of LPA receptor 1 (LPA1)
has been shown to mitigate lung injury and pulmonary fibrosis. AM966, an LPA1
antagonist exhibiting an antifibrotic property, has been considered to be a
future antifibrotic medicine. Here, we report an unexpected effect of AM966,
which increases lung endothelial barrier permeability. An electric cell-substrate
sensing (ECIS) system was used to measure permeability in human lung
microvascular endothelial cells (HLMVECs). AM966 decreased the transendothelial
electrical resistance (TEER) value immediately in a dose-dependent manner.
VE-cadherin and f-actin double immunostaining reveals that AM966 increases stress
fibers and gap formation between endothelial cells. AM966 induced phosphorylation
of myosin light chain (MLC) through activation of RhoA/Rho kinase pathway. Unlike
LPA treatment, AM966 had no effect on phosphorylation of extracellular
signal-regulated kinases (Erk). Further, in LPA1 silencing cells, we observed
that AM966-increased lung endothelial permeability as well as phosphorylation of
VE-cadherin and focal adhesion kinase (FAK) were attenuated. This study reveals
that AM966 induces lung endothelial barrier dysfunction, which is regulated by
LPA1-mediated activation of RhoA/MLC and phosphorylation of VE-cadherin.