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Apoptosis Signal-Regulating Kinase 1 (Ask1) Inhibition Prevents In Vivo Thrombosis without Compromising Hemostasis
Cardiovascular diseases are currently among the leading causes of death in mankind. Although significant progress has been made in prevention and treatment, the currently available pharmacological interventions have a significant rate of severe bleeding side effects due to their effect on hemostasis...
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Published in: | Blood 2023-11, Vol.142 (Supplement 1), p.681-681 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Cardiovascular diseases are currently among the leading causes of death in mankind. Although significant progress has been made in prevention and treatment, the currently available pharmacological interventions have a significant rate of severe bleeding side effects due to their effect on hemostasis. Recently, we have shown that apoptosis signal-regulating kinase 1 (ASK1) plays an important role in platelet activation and thrombus formation. Here, we show that two chemically distinct ASK1 inhibitors, dose-dependently inhibited thrombin-induced phosphorylation of ASK1 and its downstream effectors MKK3/4/6, p38 MAPK, and cPLA2 in human platelets, as detected by western blotting using phospho-specific antibodies. ASK1 inhibitors also dose-dependently inhibited platelet a granule release and α IIbβ 3 activation which are the readouts for inside-out signaling events as analyzed by flow cytometry. Moreover, pretreatment of human platelets with ASK1 inhibitors completely impaired clot retraction and platelet spreading on immobilized fibrinogen two events regulated by outside-in signaling. To investigate the in-vivo effect of Ask1 inhibitor on thrombus formation, we intraperitoneally injected C57BL/6 mice with Ask1 inhibitor (1mg/kg), and the blood was withdrawn at 1-, 4-, and 24-hour time points and analyzed for in vitro thrombus formation on collagen matrix under arterial flow. Ask1 inhibitor significantly decreased thrombus growth ( P |
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ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood-2023-190782 |