aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2–mediated SphK1-S1PR1-Akt signaling axis
| Autor: | Luisa J. Coronel, Hemal H. Patel, Neil Grimsey, Cisneros-Aguirre M, Mark A. Lawson, Olivia Molinar-Inglis, Anand Patwardhan, Gomez-Menzies Pk, JoAnn Trejo, Dequina A. Nicholas, Cierra A. Birch, Huilan Lin, Brian H. Chen |
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| Rok vydání: | 2021 |
| Předmět: |
Pyrrolidines
Pyridines Organophosphonates PAR-1 Apoptosis 3-Ring endothelial dysfunction chemistry.chemical_compound Lactones GPCR cytoprotection Heterocyclic Compounds Heterotrimeric G protein Caveolae Humans Receptor PAR-1 Anilides Sulfones Enzyme Inhibitors Receptor Protein kinase B Sphingosine-1-Phosphate Receptors S1PR1 biased signaling Multidisciplinary Sphingosine Chemistry Methanol Endothelial Cells Biological Sciences beta-Arrestin 2 Cell biology Phosphotransferases (Alcohol Group Acceptor) Gene Expression Regulation cardiovascular system Phosphorylation Signal transduction Heterocyclic Compounds 3-Ring Proto-Oncogene Proteins c-akt Platelet Aggregation Inhibitors Protein C |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 118, iss 49 Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Endothelial dysfunction is associated with vascular disease and results in disruption of endothelial barrier function and increased sensitivity to apoptosis. Currently, there are limited treatments for improving endothelial dysfunction. Activated protein C (aPC), a promising therapeutic, signals via protease-activated receptor-1 (PAR1) and mediates several cytoprotective responses, including endothelial barrier stabilization and anti-apoptotic responses. We showed that aPC-activated PAR1 signals preferentially via β-arrestin-2 (β-arr2) and dishevelled-2 (Dvl2) scaffolds rather than G proteins to promote Rac1 activation and barrier protection. However, the signaling pathways utilized by aPC/PAR1 to mediate anti-apoptotic activities are not known. aPC/PAR1 cytoprotective responses also require coreceptors; however, it is not clear how coreceptors impact different aPC/PAR1 signaling pathways to drive distinct cytoprotective responses. Here, we define a β-arr2-mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. Using human cultured endothelial cells, we found that endogenous PAR1 and S1PR1 coexist in caveolin-1 (Cav1)-rich microdomains and that S1PR1 coassociation with Cav1 is increased by aPC activation of PAR1. Our study further shows that aPC stimulates β-arr2-dependent SphK1 activation independent of Dvl2 and is required for transactivation of S1PR1-Akt signaling and protection against cell death. While aPC/PAR1-induced, extracellular signal-regulated kinase 1/2 (ERK1/2) activation is also dependent on β-arr2, neither SphK1 nor S1PR1 are integrated into the ERK1/2 pathway. Finally, aPC activation of PAR1-β-arr2-mediated protection against apoptosis is dependent on Cav1, the principal structural protein of endothelial caveolae. These studies reveal that different aPC/PAR1 cytoprotective responses are mediated by discrete, β-arr2-driven signaling pathways in caveolae. |
| Databáze: | OpenAIRE |
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