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aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Dec 07; Vol. 118 (49). - Publication Year :
- 2021
-
Abstract
- 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.<br />Competing Interests: The authors declare no competing interest.
- Subjects :
- Anilides pharmacology
Apoptosis physiology
Endothelial Cells physiology
Enzyme Inhibitors pharmacology
Gene Expression Regulation drug effects
Heterocyclic Compounds, 3-Ring pharmacology
Humans
Lactones pharmacology
Methanol pharmacology
Organophosphonates pharmacology
Phosphotransferases (Alcohol Group Acceptor) genetics
Platelet Aggregation Inhibitors pharmacology
Protein C genetics
Proto-Oncogene Proteins c-akt genetics
Pyridines pharmacology
Pyrrolidines pharmacology
Receptor, PAR-1 genetics
Sphingosine-1-Phosphate Receptors genetics
Sulfones pharmacology
beta-Arrestin 2 genetics
Phosphotransferases (Alcohol Group Acceptor) metabolism
Protein C metabolism
Proto-Oncogene Proteins c-akt metabolism
Receptor, PAR-1 metabolism
Sphingosine-1-Phosphate Receptors metabolism
beta-Arrestin 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 118
- Issue :
- 49
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 34873055
- Full Text :
- https://doi.org/10.1073/pnas.2106623118