L'AMPKalpha1 régule la polymérisation de l'actine, la formation des lamellipodes et la rétraction du clou plaquettaire en réponse à la thrombine
(2014)
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- Abstract
- Platelet activation requires sweeping morphological changes, supported by contraction and remodelling of platelet actin cytoskeleton. In epithelial and endothelial cells, AMP-activated protein kinase (AMPK) controls actin cytoskeleton organization through the phosphorylation of cytoskeletal targets, namely myosin regulatory light chains (MLC), cofilin and the vasodilator-stimulated phosphoprotein (VASP), extending the role of AMPK beyond metabolism. In this thesis, we hypothesized that AMPK was activated in thrombin-stimulated platelets and played a role in platelet secretion, aggregation and clot retraction, by regulating polymerization and/or organization of actin cytoskeleton through the phosphorylation of MLC, cofilin and VASP. We show that human platelets expressed exclusively the AMPKα1 isoform. In human purified platelets, thrombin led to a transient activation of AMPKα1 and to phosphorylation of its substrate acetyl coA carboxylase (ACC). Platelets isolated from mice lacking AMPKα1 exhibited reduced aggregation and secretion in response to thrombin, associated with a defect in ACC, MLC, cofilin and VASP phosphorylation. These changes were associated with an abrogation of thrombin-dependent F-actin formation. Moreover, the percentage of platelets able to form lamellipodia after immobilization on fibrinogen-coated coverslips and stimulation by thrombin, was significantly reduced in the absence of AMPKα1, indicating an altered cytoskeleton reorganization during spreading. More importantly, clot retraction was slower and less effective in KO platelets. Conclusion: AMPKα1 plays a critical role in platelet function in response to thrombin through the phosphorylation of cytoskeletal targets and the subsequent regulation of cytoskeleton organization -dependent processes. This conclusion is supported by clinical data showing that AMPK is also activated in vivo, in platelets of patients undergoing cardiac surgery and therefore submitted to a thrombotic process designed to counter bleeding.
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Onselaer, M.-B. (2014). L’AMPKalpha1 régule la polymérisation de l’actine, la formation des lamellipodes et la rétraction du clou plaquettaire en réponse à la thrombine. https://hdl.handle.net/2078.5/193544