Abstract Number: PB1754
Meeting: ISTH 2020 Congress
Background: We previously showed that constitutively activated acetyl-CoA carboxylase (ACC) promotes platelet activation and thrombus formation by increasing platelet phospholipid content. ACC carboxylates acetyl-CoA into malonyl-CoA, the precursor of de novo lipogenesis. Inhibition of its activity decreases lipogenesis. The concomitant increase in acetyl-CoA can serve as a substrate for protein acetylation. This posttranslational modification plays a key role in the regulation of platelet functions, especially on platelet aggregation, shape change and spreading kinetics via tubulin acetylation.
Aims: We postulate that ACC inhibition might affect platelet functions via an alteration of lipid content and/or tubulin acetylation.
Methods: Platelets were incubated for 2 hours with CP640.186, an ACC inhibitor, before thrombin stimulation. Platelet functions were assessed by aggregometry, flow cytometry and adhesion studies. Lipogenesis was measured via 14C-acetate incorporation into fatty acids. Lipidomics analysis was carried out on the commercial Lipidyzer platform. Protein phosphorylation and acetylation were evaluated by western blot.
Results: Treatment with CP640.186 drastically decreases platelet lipogenesis. Surprisingly, the quantitative lipidomics analyses showed that a 2 hours preincubation with the compound did not affect global platelet lipid content. However, the short-term ACC inhibition (and potential acetyl-CoA accumulation) was sufficient to modify the level of tubulin acetylation, at the basal state or after thrombin stimulation. It is associated with a default of platelet aggregation in response to low concentration of thrombin, and a faster platelet spreading on fibrinogen-coated surface. Mechanistically, we highlighted a decrease in PAK2 phosphorylation, a key regulator of actin and microtubule remodeling.
Conclusions: Pharmacological ACC inhibition by CP640.186 decreases platelet aggregation and affects the kinetics of platelet spreading upon thrombin stimulation. The underlying mechanism does not involve a change in lipid content but may depend on tubulin acetylation, subsequent alteration of PAK2 signaling and downstream actin and/or microtubule remodeling.
To cite this abstract in AMA style:Octave M, Ginion A, Pirotton L, Robaux V, Lepropre S, Kautbally S, Darley-Usmar VM, Ambroise J, Guigas B, Giera M, Foretz M, Bertand L, Beauloye C, Horman S. Acetyl-CoA Carboxylase Inhibition Alters Tubulin Acetylation and Aggregation in Thrombin-stimulated Platelets [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/acetyl-coa-carboxylase-inhibition-alters-tubulin-acetylation-and-aggregation-in-thrombin-stimulated-platelets/. Accessed January 27, 2022.
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