Abstract 382: Oxidized LDL Signaling “Primes” GPVI-Mediated Platelet Activation in a CD36-Dependent Manner
CD36 acts as an important participant in the prothrombotic state associated with chronic inflammatory diseases such as atherosclerosis and diabetes by serving as a signaling relay point for danger-associated molecular patterns (DAMPs), including oxidized low-density lipoproteins (oxLDL) and advanced glycated proteins. Although CD36-mediated signaling pathways have been well characterized in macrophages, less is known about CD36-mediated signaling in platelets. Our group identified important roles for specific Src family kinases (SFK) Lyn and Fyn, and for the guanine nucleotide exchange factors Vav1 and Vav3. Since platelet activation by the collagen receptor GPVI also involves downstream activation of SFKs, we now hypothesize that oxLDL signaling via CD36 primes platelets for hyperactivity by activating components of the GPVI signaling pathway. To test this hypothesis, we treated fluorescently labeled murine platelets with either native LDL (nLDL) or oxLDL and exposed them to immobilized collagen under defined shear flow in a microfluidic flow chamber. A significant increase (~1.2 fold) in platelet accumulation was observed with oxLDL treatment. No increase in accumulation was observed in oxLDL-treated platelets from cd36 null mice, suggesting that this phenomenon was CD36-dependent. Furthermore, addition of tirofiban ablated the oxLDL-induced increase in platelet accumulation, suggesting that the increase was likely due to enhanced platelet-platelet contacts (i.e. enhanced platelet activation). This supports previous data from our laboratory showing that treatment of murine platelets with oxLDL alone resulted in activation of αIIbβ3 integrin. Additionally, oxLDL-treated platelets from vav1/vav3 double null mice phenocopied cd36 null platelets and displayed no increase in platelet accumulation compared to nLDL-treated platelets, strengthening the functional link between CD36 and GPVI signaling pathways. These data suggest a functional link between CD36 and GPVI signaling pathways in platelets, which may contribute to platelet hyperactivity in athero-inflammatory diseases.
Author Disclosures: G. Kartz: None. M. Yang: None. A. Sanchez: None. R. Silverstein: None.
- © 2014 by American Heart Association, Inc.