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Apolipoprotein E Receptor 2 Mediates Activated Protein C–Induced Endothelial Akt Activation and Endothelial Barrier Stabilization
| Content Provider | Scilit |
|---|---|
| Author | Sinha, Ranjeet K. Yang, Xia V. Fernandez, Jose Xu, Xiao Mosnier, Laurent O. Griffin, John H. |
| Copyright Year | 2016 |
| Description | Journal: Arteriosclerosis, thrombosis, and vascular biology Objective—: Activated protein C (APC), a plasma serine protease, initiates cell signaling that protects endothelial cells from apoptosis and endothelial barrier disruption. Apolipoprotein E receptor 2 (ApoER2; LRP8 ) is a receptor known for mediating signaling initiated by reelin in neurons. ApoER2 contributes to APC-initiated signaling in monocytic U937 cells. The objective was to determine whether ApoER2 is required for APC’s beneficial signaling in the endothelial cell surrogate EA.hy926 line. Approach and Results—: We used small interfering RNA and inhibitors to probe requirements for specific receptors for APC’s antiapoptotic activity and for phosphorylation of disabled-1 by Src family kinases and of Akt. When small interfering RNA for ApoER2 or endothelial cell protein C receptor or protease activated receptor 1 was used, APC’s antiapoptotic activity was ablated, indicating that each of these receptors was required. In EA.hy926 cells, APC induced a 2- to 3-fold increased phosphorylation of Ser473-Akt and Tyr232-disabled-1, a phosphorylation known to trigger disabled-1–mediated signaling in other cell types. Ser473-Akt phosphorylation was inhibited by ApoER2 small interfering RNA or by inhibitors of Src (PP2), phosphatidylinositol-3 kinase (LY303511), and protease activated receptor 1 (SCH79797). ApoER2 small interfering RNA blocked the ability of APC to prevent thrombin-induced endothelial barrier disruption in TransEndothelial Resistance assays. Binding studies using purified APC and purified immobilized wild-type and mutated ApoER2 ectodomains suggested that APC binding involves Lys49, Asp50, and Trp64 on the surface of the N-terminal LA1 domain of ApoER2. Conclusions—: ApoER2 contributes cooperatively with endothelial cell protein C receptor and protease activated receptor 1 to APC-initiated endothelial antiapoptotic and barrier protective signaling. |
| Related Links | https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.115.306795 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816599/pdf |
| Ending Page | 524 |
| Page Count | 7 |
| Starting Page | 518 |
| ISSN | 10795642 |
| e-ISSN | 15244636 |
| DOI | 10.1161/atvbaha.115.306795 |
| Journal | Arteriosclerosis, thrombosis, and vascular biology |
| Issue Number | 3 |
| Volume Number | 36 |
| Language | English |
| Publisher | Ovid Technologies (Wolters Kluwer Health) |
| Publisher Date | 2016-03-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Arteriosclerosis, thrombosis, and vascular biology Endocrinology and Metabolism Apolipoprotein E Receptor 2 Signal Transduction Endothelial Cells Protein C Low Density Lipoprotein Receptor-related Protein 8 |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cardiology and Cardiovascular Medicine |
