期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 12, 期 8, 页码 1331-1341出版社
WILEY
DOI: 10.1111/jth.12619
关键词
antibodies; G-protein-coupled receptors; hemostasis; platelet aggregation inhibitors; protease-activated receptor-4 protein, human; thrombosis
资金
- American Heart Association (AHA Beginning Grant In Aid) [0865441D]
- American Heart Association (AHA Scientist Development Grant) [10SDG2600021]
- American Society for Hematology (ASH Scholar Award)
- NIH [HL098217]
- Cardiovascular Training Grant [5T32HL105338]
- CWRU/UH Center for AIDS Research [NIH P30 AI036219]
Background: Human platelet activation and aggregation is a complex process. To date, many therapies have been developed targeting proteins that mediate this process to prevent unwanted activation. However, the current standard of care for acute coronary syndromes still has limitations, including bleeding risk. Objective: To evaluate the protease-activated receptor 4 (PAR4) anionic cluster as a viable antiplatelet target by using a polyclonal antibody (CAN12). Methods: We used western blotting, aggregation and secretion ex vivo to evaluate the ability of CAN12 to interact with PAR4 and inhibit platelet activation. The effects of CAN12 in vivo were evaluated with the Rose Bengal arterial thrombosis model and two models of hemostasis. Results: CAN12 was able to interact with human PAR4 and delay PAR4 cleavage. In addition, CAN12 inhibited thrombin-induced human platelet aggregation and secretion in a dose-dependent manner. The specificity of CAN12 was agonist-dependent. In vivo, we determined that CAN12 was able to inhibit arterial thrombosis, and, using two independent methods, we found that CAN12 did not influence hemostasis. Conclusion: Targeting the extracellular anionic cluster on PAR4 is a viable novel strategy as an antiplatelet therapy.
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