Platelet CD36 promotes thrombosis by activating redox sensor ERK5 in hyperlipidemic conditions

Moua Yang, Brian C. Cooley, Wei Li, Yiliang Chen, Jeannette Vasquez-Vivar, Na’il O. Scoggins, Scott J. Cameron, Craig N. Morrell and Roy L. Silverstein

Key Points

  • Atherogenic conditions promote platelet CD36 signaling by generating specific reactive oxygen species.

  • Redox sensor ERK5 MAP kinase activation by reactive oxygen species potentiates thrombus formation in hyperlipidemic conditions.


Atherothrombosis is a process mediated by dysregulated platelet activation that can cause life-threatening complications and is the leading cause of death by cardiovascular disease. Platelet reactivity in hyperlipidemic conditions is enhanced when platelet scavenger receptor CD36 recognizes oxidized lipids in oxidized low-density lipoprotein (oxLDL) particles, a process that induces an overt prothrombotic phenotype. The mechanisms by which CD36 promotes platelet activation and thrombosis remain incompletely defined. In this study, we identify a mechanism for CD36 to promote thrombosis by increasing activation of MAPK extracellular signal-regulated kinase 5 (ERK5), a protein kinase known to be exquisitely sensitive to redox stress, through a signaling pathway requiring Src kinases, NADPH oxidase, superoxide radical anion, and hydrogen peroxide. Pharmacologic inhibitors of ERK5 blunted platelet activation and aggregation in response to oxLDL and targeted genetic deletion of ERK5 in murine platelets prevented oxLDL-induced platelet deposition on immobilized collagen in response to arterial shear. Importantly, in vivo thrombosis experiments after bone marrow transplantation from platelet-specific ERK5 null mice into hyperlipidemic apolipoprotein E null mice showed decreased platelet accumulation and increased thrombosis times compared with mice transplanted with ERK5 expressing control bone marrows. These findings suggest that atherogenic conditions critically regulate platelet CD36 signaling by increasing superoxide radical anion and hydrogen peroxide through a mechanism that promotes activation of MAPK ERK5.

  • Submitted November 7, 2016.
  • Accepted March 13, 2017.
View Full Text