Oxidized LDL-bound CD36 recruits an Na⁺/K⁺-ATPase-Lyn complex in macrophages that promotes atherosclerosis. Sci Signal 2015 Sep 08;8(393):ra91
Date
09/10/2015Pubmed ID
26350901Pubmed Central ID
PMC4852751DOI
10.1126/scisignal.aaa9623Scopus ID
2-s2.0-84941034207 (requires institutional sign-in at Scopus site) 73 CitationsAbstract
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.
Author List
Chen Y, Kennedy DJ, Ramakrishnan DP, Yang M, Huang W, Li Z, Xie Z, Chadwick AC, Sahoo D, Silverstein RLAuthors
Yiliang Chen PhD Assistant Professor in the Medicine department at Medical College of WisconsinDaisy Sahoo PhD Dean, Professor in the Medicine department at Medical College of Wisconsin
Roy L. Silverstein MD Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAtherosclerosis
CD36 Antigens
Lipoproteins, LDL
Macrophages
Mice
Mice, Knockout
Sodium-Potassium-Exchanging ATPase
src-Family Kinases
