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Atherogenic lipid stress induces platelet hyperactivity through CD36-mediated hyposensitivity to prostacyclin-; the role of phosphodiesterase 3A.

Berger, Martin; Raslan, Zaher; Aburima, Ahmed; Magwenzi, Simbarashe; Wraith, Katie S.; Spurgeon, Benjamin E.J.; Hindle, Matthew S.; Law, Robert; Febbraio, Maria; Naseem, Khalid M.

Authors

Martin Berger

Zaher Raslan

Ahmed Aburima

Simbarashe Magwenzi

Katie S. Wraith

Benjamin E.J. Spurgeon

Matthew S. Hindle

Robert Law

Maria Febbraio

Khalid M. Naseem



Abstract

©2020 Ferrata Storti Foundation Prostacyclin (PGI2) controls platelet activation and thrombosis through a cyclic adenosine monophosphate (cAMP) signaling cascade. However, in patients with cardiovascular diseases this protective mechanism fails for reasons that are unclear. Using both pharmacological and genetic approaches we describe a mechanism by which oxidized low density lipoproteins (oxLDL) associated with dyslipidemia promote platelet activation through impaired PGI2 sensitivity and diminished cAMP signaling. In functional assays using human platelets, oxLDL modulated the inhibitory effects of PGI2, but not a phosphodiesterase (PDE)-insensitive cAMP analog, on platelet aggregation, granule secretion and in vitro thrombosis. Examination of the mechanism revealed that oxLDL promoted the hydrolysis of cAMP through the phosphorylation and activation of PDE3A, leading to diminished cAMP signaling. PDE3A activation by oxLDL required Src family kinases, Syk and protein kinase C. The effects of oxLDL on platelet function and cAMP signaling were blocked by pharmacological inhibition of CD36, mimicked by CD36-specific oxidized phospholipids and ablated in CD36-/- murine platelets. The injection of oxLDL into wild-type mice strongly promoted FeCl3-induced carotid thrombosis in vivo, which was prevented by pharmacological inhibition of PDE3A. Furthermore, blood from dyslipidemic mice was associated with increased oxidative lipid stress, reduced platelet sensitivity to PGI2 ex vivo and diminished PKA signaling. In contrast, platelet sensitivity to a PDE-resistant cAMP analog remained normal. Genetic deletion of CD36 protected dyslipidemic animals from PGI2 hyposensitivity and restored PKA signaling. These data suggest that CD36 can translate atherogenic lipid stress into platelet hyperactivity through modulation of inhibitory cAMP signaling.

Citation

Berger, M., Raslan, Z., Aburima, A., Magwenzi, S., Wraith, K. S., Spurgeon, B. E., …Naseem, K. M. (2020). Atherogenic lipid stress induces platelet hyperactivity through CD36-mediated hyposensitivity to prostacyclin-; the role of phosphodiesterase 3A. Haematologica, 105(3), 808-819. https://doi.org/10.3324/haematol.2018.213348

Journal Article Type Article
Acceptance Date May 22, 2019
Online Publication Date Jul 9, 2019
Publication Date Mar 1, 2020
Deposit Date Nov 7, 2019
Publicly Available Date Nov 8, 2019
Journal Haematologica
Print ISSN 0390-6078
Electronic ISSN 1592-8721
Publisher Ferrata Storti Foundation
Peer Reviewed Peer Reviewed
Volume 105
Issue 3
Pages 808-819
DOI https://doi.org/10.3324/haematol.2018.213348
Keywords Platelets; Arterial thrombosis; CD36; Phosphodiesterase 3A; Prostacyclin
Public URL https://hull-repository.worktribe.com/output/2332973
Publisher URL http://www.haematologica.org/content/early/2019/07/08/haematol.2018.213348
Related Public URLs http://eprints.whiterose.ac.uk/149329/

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