Research ArticleVascular Disease

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

Sci. Signal.  08 Sep 2015:
Vol. 8, Issue 393, pp. ra91
DOI: 10.1126/scisignal.aaa9623

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Na+/K+-ATPase helps turn macrophages into toxic foam cells

Oxidized LDL inhibits macrophage migration and promotes lipid uptake by macrophages, which become foam cells that accumulate in atherosclerotic plaques. Chen et al. showed that CD36, the receptor for oxidized LDL, activated the tyrosine kinase Lyn in macrophages through the ion transporter Na+/K+-ATPase. Macrophages that lacked an allele encoding a subunit of the Na+/K+-ATPase were defective in responding to oxidized LDL. Apoe-null mice are prone to developing atherosclerosis when placed on a high-fat diet, and atherosclerosis development was reduced in these mice when they received macrophages lacking an allele encoding the Na+/K+-ATPase subunit.

Abstract

One characteristic of atherosclerosis is the accumulation of lipid-laden macrophage foam cells in the arterial wall. We have 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 the macrophage oxLDL-CD36 signaling axis. Using peritoneal macrophages 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 α1 Na+/K+-ATPase catalytic subunit did not respond to activation of CD36, showing attenuated oxLDL uptake and foam cell formation, and oxLDL failed to inhibit migration of these macrophages. Furthermore, Apoe-null mice, which are a model of atherosclerosis, were protected from diet-induced atherosclerosis by global deletion of a single allele encoding the α1 Na+/K+-ATPase subunit or reconstitution with macrophages that lacked an allele encoding the α1 Na+/K+-ATPase subunit. These findings identify Na+/K+-ATPase as a potential target for preventing or treating atherosclerosis.

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