Oxidised LDL activates blood platelets through CD36/NOX2-mediated inhibition of the cGMP/protein kinase G signalling cascade
Publication date
23/04/2015Author
Magwenzi, S.Woodward, C.
Wraith, K.S.
Aburima, A.
Raslan, Z.
Jones, Huw

McNeil, C.
Wheatcroft, S.
Yuldasheva, N.
Febbriao, M.
Kearney, M.
Naseem, K.M.
Keyword
Blood plateletscd36 antigens
current good manufacturing practice
Cybb gene
Cyclic gmp
low-density lipoproteins
Signal transduction
Hyperlipidemia
Cyclic gmp-dependent protein kinases
Mice
Peer-Reviewed
YesOpen Access status
closedAccessAccepted for publication
03/02/2015
Metadata
Show full item recordAbstract
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.Version
No full-text in the repositoryCitation
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 Version of Record
https://doi.org/10.1182/blood-2014-05-574491Type
Articleae974a485f413a2113503eed53cd6c53
https://doi.org/10.1182/blood-2014-05-574491