Oxidized LDL-bound CD36 recruits an Na⁺/K⁺-ATPase-Lyn complex in macrophages that promotes atherosclerosis.
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.
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA.
Yiliang
Y
Chen
Department of Medicine, University of Toledo, Health Science Campus, Toledo, OH 43614, USA.
David J
DJ
Kennedy
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA. Department of Molecular Medicine, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
Devi Prasadh
DP
Ramakrishnan
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Moua
M
Yang
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA.
Wenxin
W
Huang
Department of Physiology and Pharmacology, University of Toledo, Health Science Campus, Toledo, OH 43614, USA.
Zhichuan
Z
Li
Department of Physiology and Pharmacology, University of Toledo, Health Science Campus, Toledo, OH 43614, USA.
Zijian
Z
Xie
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Alexandra C
AC
Chadwick
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Daisy
D
Sahoo
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA. Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA. rsilverstein@mcw.edu.
Roy L
RL
Silverstein
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D018955:CD36 Antigens; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C497344:Atp1a1 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase