Oxidized LDL-bound CD36 recruits an Na+/K+-ATPase-Lyn complex in macrophages that promotes atherosclerosis

Abstract

One characteristic of atherosclerosis is the accumulation of lipid-laden macrophage foamcells in the arterial wall.Wehave previously shown that the binding of oxidized low-density lipoprotein (oxLDL) to the scavenger receptor CD36 activates the kinase Lyn, initiating a cascade that inhibits macrophage migration and is necessary for foam cell generation.We identified the plasma membrane ion transporter Na+/K+-ATPase as a key component in themacrophage oxLDL-CD36signaling axis. Using peritonealmacrophages isolated from Atp1a1 heterozygous or Cd36-null mice, we demonstrated that CD36 recruited an Na+/K+-ATPase-Lyn complex for Lyn activation in response to oxLDL. Macrophages deficient in the a1 Na+/K+-ATPase catalytic subunit did not respond to activation of CD36, showing attenuated oxLDL uptake and foam cell formation, and oxLDL failed to inhibitmigration of thesemacrophages. Furthermore,Apoe-nullmice, which are amodel of atherosclerosis, were protected from diet-induced atherosclerosis by global deletion of a single allele encoding the α1Na+/K+-ATPase subunit or reconstitution with macrophages that lacked an allele encoding the a1Na+/K+-ATPase subunit. These findings identify Na+/K+-ATPase as a potential target for preventing or treating atherosclerosis.