Page 294 - Haematologica March 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):808-819
Platelet Biology & its Disorders
Atherogenic lipid stress induces platelet hyperactivity through CD36-mediated hyposensitivity to prostacyclin: the role of phosphodiesterase 3A
Martin Berger,1,2,3 Zaher Raslan,3* Ahmed Aburima,1* Simbarashe Magwenzi,1 Katie S. Wraith,1 Benjamin E.J. Spurgeon,3 Matthew S. Hindle,3 Robert Law,1 Maria Febbraio4 and Khalid M. Naseem1,3
1
Centre for Cardiovascular and Metabolic Research, Hull York Medical School, University of Hull, Hull, UK; 2Department of Internal Medicine 1, University Hospital RWTH Aachen, Aachen, Germany; 3Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK and 4School of Dentistry, University of Alberta, Edmonton, AB, Canada
*ZR and AA contributed equally to this work
ABSTRACT
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 signal- ing. 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 throm- bosis. 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 dimin- ished PKA signaling. In contrast, platelet sensitivity to a PDE-resistant cAMP analog remained normal. Genetic deletion of CD36 protected dys- lipidemic 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.
Introduction
Myocardial infarction (MI) is characterized by platelet-driven atherothrombotic events that lead to acute occlusion of a coronary vessel. Excessive platelet activation is controlled by endothelial derived nitric oxide (NO) and prostacyclin (PGI2),1 but action of these protective agents is overcome in MI by mechanisms that are yet to be elucidated. A key risk factor for MI is dyslipidemia, which is strongly associated with a pro-thrombotic phenotype linked to atherothrombosis and platelet hyperac- tivity.2,3 The blood of high-risk individuals with dyslipidemia is characterized by increased plasma lipid peroxides, with low density lipoproteins (LDL) serving as a highly abundant carriers for these oxidatively-modified lipids.4–6 Oxidized LDL (oxLDL) are circulating pathological ligands that can enhance thrombosis through
Correspondence:
KHALID M. NASEEM
k.naseem@leeds.ac.uk
Received: December 19, 2018. Accepted: July 4, 2019. Pre-published: June 9, 2019.
doi:10.3324/haematol.2018.213348
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/808
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