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    Oxidised LDL activates blood platelets through CD36/NOX2-mediated inhibition of the cGMP/protein kinase G signalling cascade

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    Publication date
    2015-04-23
    Author
    Magwenzi, S.
    Woodward, C.
    Wraith, K.S.
    Aburima, A.
    Raslan, Z.
    Jones, Huw S.
    McNeil, C.
    Wheatcroft, S.
    Yuldasheva, N.
    Febbriao, M.
    Kearney, M.
    Naseem, K.M.
    Show allShow less
    Keyword
    Blood platelets
    cd36 antigens
    current good manufacturing practice
    Cybb gene
    Cyclic gmp
    low-density lipoproteins
    Signal transduction
    Hyperlipidemia
    Cyclic gmp-dependent protein kinases
    Mice
    Peer-Reviewed
    Yes
    
    Metadata
    Show full item record
    Abstract
    Oxidized low-density lipoprotein (oxLDL) promotes unregulated platelet activation in dyslipidemic disorders. Although oxLDL stimulates activatory signaling, it is unclear how these events drive accelerated thrombosis. Here, we describe a mechanism for oxLDL-mediated platelet hyperactivity that requires generation of reactive oxygen species (ROS). Under arterial flow, oxLDL triggered sustained generation of platelet intracellular ROS, which was blocked by CD36 inhibitors, mimicked by CD36-specific oxidized phospholipids, and ablated in CD36(-/-) murine platelets. oxLDL-induced ROS generation was blocked by the reduced NAD phosphate oxidase 2 (NOX2) inhibitor, gp91ds-tat, and absent in NOX2(-/-) mice. The synthesis of ROS by oxLDL/CD36 required Src-family kinases and protein kinase C (PKC)-dependent phosphorylation and activation of NOX2. In functional assays, oxLDL abolished guanosine 3',5'-cyclic monophosphate (cGMP)-mediated signaling and inhibited platelet aggregation and arrest under flow. This was prevented by either pharmacologic inhibition of NOX2 in human platelets or genetic ablation of NOX2 in murine platelets. Platelets from hyperlipidemic mice were also found to have a diminished sensitivity to cGMP when tested ex vivo, a phenotype that was corrected by infusion of gp91ds-tat into the mice. This study demonstrates that oxLDL and hyperlipidemia stimulate the generation of NOX2-derived ROS through a CD36-PKC pathway and may promote platelet hyperactivity through modulation of cGMP signaling.
    URI
    http://hdl.handle.net/10454/17793
    Version
    No full-text in the repository
    Citation
    Magwenzi S, Woodward C, Wraith KS et al (2015) Oxidised LDL activates blood platelets through CD36/NOX2-mediated inhibition of the cGMP/protein kinase G signalling cascade. Blood. 125(17): 2693-2703.
    Link to publisher’s version
    https://doi.org/10.1182/blood-2014-05-574491
    Type
    Article
    Collections
    Life Sciences Publications

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