Abstract 639: CD36 Recruits Na/K-ATPase/Lyn Complex to Mediate Proatherogenic Phenotypes in Macrophages

Atherosclerosis is characterized by accumulation of macrophage foam cells in the arterial wall. We previously showed that CD36, a scavenger receptor highly expressed in macrophages, mediates oxidized-LDL (oxLDL) uptake, contributes to intracellular cholesterol accumulation and foam cell formation, and regulates macrophage migration and pro-inflammatory signaling. Genetic deletion of cd36 in mice is protective against diet-induced atherosclerosis. Mechanistically, we discovered that binding of oxLDL to CD36 activates Lyn kinase and initiates a cascade that is necessary for the pro-atherogenic cellular phenotype. Nevertheless, how CD36 regulates Lyn kinase remains undefined. We previously showed that Na/K-ATPase (NKA) regulates Src family kinases, including Lyn and we now hypothesized that CD36 regulates Lyn kinase via an interaction with NKA. We used co-immunoprecipitation and a novel immunofluorescence-based cell surface cross linking assay to demonstrate that CD36 physically associates with NKA on the macrophage surface. In a NKA α1 subunit heterozygous null mouse model in which ~60% of macrophage NKA expression is downregulated, we demonstrated that recruitment and activation of Lyn and its downstream signaling events in response to oxLDL were abolished. Functionally, we showed that NKA haploinsufficiency significantly blunted oxLDL uptake, foam cell formation and macrophage migration under atherogenic conditions. Importantly NKA α1 heterozygous null mice when bred into an apoe null background developed less atherosclerosis (26.7% lesion area in NKA control mice v.s. 13.4% lesion area in NKA heterozygous null mice) assessed by en face oil red O staining of aortae after 12 weeks on high fat diet. We conclude that by controlling Lyn kinase activity NKA critically regulates oxLDL/CD36 induced pro-atherogenic signaling.