The scavenger receptor CD36 links atherogenic dyslipidemia to platelet hyperactivity and accelerated thrombosis through the binding of oxidized low-density lipoproteins (oxLDL). The signaling mechanism(s) that facilitates CD36 translation of oxidative lipid stress into platelet activation is unclear. We examined the role of immunoreceptor tyrosine-based activation motif (ITAM) adapter proteins in CD36-mediated platelet activity. oxLDL induced the phosphorylation of the ITAM-containing adapter Fc receptor γ-chain (FcRγ) in human and murine platelets. Phosphorylation of FcRγ was blocked by Src family kinase (SFK) inhibitors, mimicked by CD36-specific oxidized phospholipids and ablated in CD36−/− murine platelets. Under basal conditions, a pool of CD36 formed a multiprotein complex that included FcRγ and the SFKs Lyn and Fyn. CD36 ligation by oxLDL resulted in the recruitment, phosphorylation, and activation of the tyrosine kinase Syk. To explore the functional cooperativity of this CD36-FcRγ complex, we used murine platelets deficient in FcRγ. The genetic ablation of FcRγ prevented oxLDL-induced tyrosine phosphorylation of Syk and downstream adapter SLP-76, but not SFKs. Moreover, platelet aggregation, in vitro thrombosis, and in vivo carotid thrombosis stimulated by oxLDL were lost in the absence of FcRγ. This study establishes FcRγ as a first functional coreceptor for CD36 in platelets, which enables lipid platelet hyperactivity and arterial thrombosis.

In the vascular system, pathological conditions that cause hypoxia are associated with increased platelet activity and thrombosis. Using a platelet spreading assay, we show that severe hypoxia (i.e., 1%), venous (i.e., 5%), and, surprisingly, arterial (i.e., 12%) oxygen concentrations cause a significant reduction in platelet surface area coverage on fibrinogen in comparison to atmospheric oxygen condition (i.e., 21% oxygen), whilst adhesion and spreading on collagen and CRP were not affected. Importantly, the addition of thrombin or zinc restored full platelet spreading on fibrinogen, indicating that the inhibition of platelet spreading on fibrinogen was due to defective integrin activation. Analysis of integrin activation with FACs via PAC-1 staining supported a significant reduction in integrin activation in hypoxic conditions. Interestingly, a fibrinogen matrix prepared at 1%, 5%, or 12% oxygen failed to induce full platelet spreading, even when the experiments were performed at atmospheric oxygen concentration, indicating that the structure and activity of the fibrinogen coating is affected by oxygen. The effect of oxygen on different matrix proteins is critical to understand, as these data clearly demonstrate that collagen and CRP can support platelet activation at all O₂ concentrations, whilst fibrinogen mediated platelet activation and spreading is lost at physiological and pathological O₂ concentrations. These data have clear implications for thrombus formation data and highlight the role of oxygen in regulating platelet function.

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide despite major advances in prevention, diagnosis and treatment

Cardiovascular diseases remain the leading cause of death worldwide despite major advances in prevention, diagnosis and treatment. This Reprint brings together a collection of research studies and narrative reviews spanning cardiovascular metabolism, inflammation, cellular signalling, vascular remodelling and gene regulation, highlighting emerging therapeutic opportunities spanning multiple cardiovascular pathologies.