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

Abstract

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.

Platelet MAPKs—a 20+ year history: What do we really know?

“…In platelets, ERK5 is activated in response to agonist stimulation 47,74,87 . When platelets were stimulated with botrocetin/vWF, ERK5 activation was blocked by inhibiting SFKs or RAFs 23 .…”

Plasma Purification is Associated With Reduced Inflammation Factors and Down-regulation of Lipid Metabolic and ER Stress Proteins in Patients With Hyperlipidemia

“…CD36 expression was increased in patients with hypercholesterolemia [20]. Previous study showed that CD36 promoted cell uptake of free fatty acids and regulated intestinal cholesterol synthesis [21], also ox-LDL could induce platelet activation, ROS production, nally resulted in thrombosis via CD36 and MAPK pathways [22][23][24]. In vivo study, it was observed that insulin resistance and in ammatory factors release reduced in CD36 knockout mice, indicating CD36 plays an important role in health human [25].…”

Platelet lipidome: Dismantling the “Trojan horse” in the bloodstream

“…LDL/oxLDL triggers intraplatelet ROS generation, like in the oxLDL‐CD36 axis; induces lipid peroxidation; and LDL modifications, which enriches the repertoire of oxidized lipids . OxLDL‐CD36 potentiates arterial thrombosis in hyperlipidemic ApoE −/− mice through activation of redox‐sensitive ERK5 . This eventually promotes externalization of thrombogenic‐PL, PS, in a caspase‐dependent manner, followed by assembly of the prothrombinase complex and fibrin generation (Figure ) .…”

“…5 OxLDL-CD36 potentiates arterial thrombosis in hyperlipidemic ApoE −/− mice through activation of redox-sensitive ERK5. 32 This eventually promotes externalization of thrombogenic-PL, PS, in a caspase-dependent manner, followed by assembly of the prothrombinase complex and fibrin generation ( Figure 1). 33 Extracellular conversion of LDL to oxLDL ( Figure 1) is seen in the microenvironment of stimulated platelets; in carotid plaque homogenate; even more so with platelets from hyperlipidemic individuals, but not from patients with X-linked chronic granulomatous disease lacking NOX2, suggesting a ROS-mediated process.…”