AM966, an Antagonist of Lysophosphatidic Acid Receptor 1, Increases Lung Microvascular Endothelial Permeability through Activation of Rho Signaling Pathway and Phosphorylation of VE-Cadherin
| Autor: | Jianxin Wei, Shuang Li, Junting Cai, Tomeka Suber, Jing Zhao |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway RHOA Article Subject Immunology Lung injury Biology Cell Line Focal adhesion Capillary Permeability 03 medical and health sciences chemistry.chemical_compound Antigens CD Lysophosphatidic acid lcsh:Pathology Humans Phosphorylation Receptors Lysophosphatidic Acid Extracellular Signal-Regulated MAP Kinases Rho-associated protein kinase Lung Phenylacetates Kinase Cell Biology Cadherins 3. Good health Cell biology 030104 developmental biology chemistry Focal Adhesion Protein-Tyrosine Kinases biology.protein Carbamates rhoA GTP-Binding Protein lcsh:RB1-214 Research Article Signal Transduction |
| Zdroj: | Mediators of Inflammation Mediators of Inflammation, Vol 2017 (2017) |
| ISSN: | 1466-1861 0962-9351 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text