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Characterization of a Novel Function-Blocking Antibody Targeted Against the Platelet P2Y$ _{1}$ Receptor
| Content Provider | Scilit |
|---|---|
| Author | Karim, Zubair A. Vemana, Hari Priya Alshbool, Fatima Z. Lin, Olivia A. Alshehri, Abdullah M. Javaherizadeh, Payam Espinosa, Enma V. Paez Khasawneh, Fadi T. |
| Copyright Year | 2015 |
| Description | Journal: Arteriosclerosis, thrombosis, and vascular biology Objective—: Platelet hyperactivity is associated with vascular disease and contributes to the genesis of thrombotic disorders. ADP plays an important role in platelet activation and activates platelets through 2 G-protein–coupled receptors, the Gq-coupled P2Y$ _{1}$ receptor (P2Y$ _{1}$ R), and the Gi-coupled P2Y$ _{12}$ receptor. Although the involvement of the P2Y$ _{1}$ R in thrombogenesis is well established, there are no antagonists that are currently available for clinical use. Approach and Results—: Our goal is to determine whether a novel antibody targeting the ligand-binding domain, ie, second extracellular loop (EL2) of the P2Y$ _{1}$ R (EL2Ab) could inhibit platelet function and protect against thrombogenesis. Our results revealed that the EL2Ab does indeed inhibit ADP-induced platelet aggregation, in a dose-dependent manner. Furthermore, EL2Ab was found to inhibit integrin GPIIb-IIIa activation, dense and α granule secretion, and phosphatidylserine exposure. These inhibitory effects translated into protection against thrombus formation, as evident by a prolonged time for occlusion in a FeCl$ _{3}$ -induced thrombosis model, but this was accompanied by a prolonged tail bleeding time. We also observed a dose-dependent displacement of the radiolabeled P2Y$ _{1}$ R antagonist [$ ^{3}$ H]MRS2500 from its ligand-binding site by EL2Ab. Conclusions—: Collectively, our findings demonstrate that EL2Ab binds to and exhibits P2Y$ _{1}$ R-dependent function-blocking activity in the context of platelets. These results add further evidence for a role of the P2Y$ _{1}$ R in thrombosis and validate the concept that targeting it is a relevant alternative or complement to current antiplatelet strategies. |
| Related Links | https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.114.304509 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344398/pdf https://www.ahajournals.org/doi/reader/10.1161/ATVBAHA.114.304509 |
| Ending Page | 644 |
| Page Count | 8 |
| Starting Page | 637 |
| ISSN | 10795642 |
| e-ISSN | 15244636 |
| DOI | 10.1161/atvbaha.114.304509 |
| Journal | Arteriosclerosis, thrombosis, and vascular biology |
| Issue Number | 3 |
| Volume Number | 35 |
| Language | English |
| Publisher | Ovid Technologies (Wolters Kluwer Health) |
| Publisher Date | 2015-03-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Arteriosclerosis, thrombosis, and vascular biology Biochemistry and Molecular Biology Antithrombotic Agents Blood Platelets P2y1 Receptor Antagonists Platelet Inhibitors Antiplatelet Agents |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cardiology and Cardiovascular Medicine |
