Inhibition of Platelet Aggregation by Activation of Platelet Intermediate Conductance Ca2+-Activated Potassium Channels

Valentina Back; Amir Asgari; Aleksandra Franczczak; Max Saito; Diego Castaneda Zaragoza; Shaun Sandow; Frances Plane; Paul Jurasz

doi:10.1111/jth.15827

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Inhibition of Platelet Aggregation by Activation of Platelet Intermediate Conductance Ca2+-Activated Potassium Channels

Journal article

Open access

Peer reviewed

Inhibition of Platelet Aggregation by Activation of Platelet Intermediate Conductance Ca2+-Activated Potassium Channels

Valentina Back, Amir Asgari, Aleksandra Franczczak, Max Saito, Diego Castaneda Zaragoza, Shaun Sandow, Frances Plane and Paul Jurasz

Journal of Thrombosis and Haemostasis, Vol.20(11), pp.2587-2600

2022

DOI: https://doi.org/10.1111/jth.15827

PMID: 35867883

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Abstract

platelets

platelet aggregation

intermediate conductance Ca2+-activated K+ channels

nitric oxide

thrombosis

Background: Within the vasculature platelets and endothelial cells play crucial roles in hemostasis and thrombosis. Platelets, like endothelial cells, possess intermediate conductance Ca2+-activated K+ (IKCa) channels and generate nitric oxide (NO). While NO limits platelet aggregation, the role of IKCa channels in platelet function and NO-generation has not yet been explored. Objectives: We investigated whether IKCa channel activation inhibits platelet aggregation, and per endothelial cells, enhances platelet NO production. Methods: Platelets were isolated from human volunteers. Aggregometry, confocal microscopy and a novel flow chamber model, the Quartz Crystal Microbalance (QCM) were used to assess platelet function. Flow cytometry was used to measure platelet NO production, calcium signaling, membrane potential, integrin αIIb/β3 activation, granule release, and procoagulant platelet formation. Results: Platelet IKCa channel activation with SKA-31 inhibited aggregation in a concentration-dependent manner, an effect reversed by the selective IKCa channel blocker TRAM-34. The QCM model along with confocal microscopy demonstrated that SKA-31 inhibited platelet aggregation under flow conditions. Surprisingly, IKCa activation by SKA-31 inhibited platelet NO generation, but this could be explained by a concomitant reduction in platelet calcium signaling. IKCa activation by SKA-31 also inhibited dense and alpha-granule secretion and integrin αIIb/β3 activation, but enhanced platelet phosphatidylserine surface exposure as a measure of procoagulant response. Conclusions: Platelet IKCa channel activation inhibits aggregation by reducing calcium-signaling and granule secretion, but not by enhancing platelet NO generation. IKCa channels may be novel targets for the development of anti-platelet drugs that limit atherothrombosis, but not coagulation.

Details

Title: Inhibition of Platelet Aggregation by Activation of Platelet Intermediate Conductance Ca2+-Activated Potassium Channels
Authors: Valentina Back (Author) - University of Alberta
Amir Asgari (Author) - University of Alberta
Aleksandra Franczczak (Author) - University of Alberta
Max Saito (Author) - University of Alberta
Diego Castaneda Zaragoza (Author) - University of Alberta
Shaun Sandow (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - Legacy
Frances Plane (Author) - University of Alberta
Paul Jurasz (Corresponding Author) - University of Alberta
Publication details: Journal of Thrombosis and Haemostasis, Vol.20(11), pp.2587-2600
Publisher: Wiley-Blackwell Publishing Ltd.
Date published: 2022
DOI: 10.1111/jth.15827
ISSN: 1538-7836
PMID: 35867883
Copyright note: This is the peer reviewed version of the following article: Back, V., Asgari, A., Franczak, A., Saito, M., Zaragoza, D.C., Sandow, S.L., Plane, F. and Jurasz, P. (2022), Inhibition of Platelet Aggregation by Activation of Platelet Intermediate Conductance Ca2+-Activated Potassium Channels. J Thromb Haemost. Accepted Author Manuscript. https://doi.org/10.1111/jth.15827, which has been published in final form at https://doi.org/10.1111/jth.15827. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
Organisation Unit: School of Health - Biomedicine; University of the Sunshine Coast, Queensland; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99659497302621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Hematology; Peripheral Vascular Disease

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