Abstract Number: PB0400
Meeting: ISTH 2022 Congress
Background: Platelets are anucleated blood cells with a main role in primary haemostasis and thrombosis. Rac1 is a small Rho GTPase that is activated in platelets upon stimulation with various ligands, including collagen and thrombin, which are ligands for the glycoprotein VI (GPVI) receptor. Rac1-deficient murine platelets present impaired lamellipodia formation, aggregation and reduced PLCγ2 activation, which is not dependent on the phosphorylation status of the protein. The effect of Rac1 inhibition on human platelets is less-well studied.
Aims: To investigate the role of Rac1 in GPVI-dependent human platelet activation.
Methods: Washed human platelets were stimulated by GPVI agonists (collagen and collagen-related peptide) in the presence of the Rac1-specific inhibitor EHT1864 and analysed for platelet activation, aggregation, spreading, protein phosphorylation and GPVI shedding. The effect of Rac1 inhibition on GPVI receptor clustering was studied using single-molecule super-resolution microscopy.
Results: In human platelets, the inhibition of Rac1 by EHT1864 had no significant effect on GPVI clustering on collagen fibres but decreased the ability of platelets to spread, aggregate or becoming activated in response to GPVI agonists. Additionally, in contrast to what is observed in murine Rac1-deficient platelets, EHT1864 enhanced GPVI shedding in both resting and activated platelets and reduced the phosphorylation levels of PLCγ2.
Conclusion(s): Rac1 activity is required for both human and murine platelet activation in response to GPVI-ligands, but Rac1’s mode of action differs between both species.
To cite this abstract in AMA style:Neagoe R, Stegner D, Nieswandt B, Watson S, Poulter N. Rac1 inhibition causes impaired GPVI signalling in human platelets through GPVI shedding and loss of PLCγ2 phosphorylation [abstract]. https://abstracts.isth.org/abstract/rac1-inhibition-causes-impaired-gpvi-signalling-in-human-platelets-through-gpvi-shedding-and-loss-of-plc%ce%b32-phosphorylation/. Accessed December 6, 2023.
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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/rac1-inhibition-causes-impaired-gpvi-signalling-in-human-platelets-through-gpvi-shedding-and-loss-of-plc%ce%b32-phosphorylation/