Oxidized LDL-bound CD36 recruits an Na⁺/K⁺-ATPase-Lyn complex in macrophages that promotes atherosclerosis.
Oxidized LDL-bound CD36 recruits an Na⁺/K⁺-ATPase-Lyn complex in macrophages that promotes atherosclerosis.
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DOI：
10.1126/scisignal.aaa9623
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发表时间：
2015-09-08
影响因子：
7.3
通讯作者：
Silverstein RL
中科院分区：
文献类型：
--
作者：
Chen Y;Kennedy DJ;Ramakrishnan DP;Yang M;Huang W;Li Z;Xie Z;Chadwick AC;Sahoo D;Silverstein RL
动脉粥样硬化的特征之一是动脉壁中富含脂质的巨噬细胞泡沫细胞的积累。我们之前已经证明，氧化低密度脂蛋白 (oxLDL) 与清道夫受体 CD36 的结合会激活激酶 Lyn，启动抑制巨噬细胞迁移的级联反应，这对于泡沫细胞的生成是必需的。在这里，我们确定质膜离子转运蛋白 Na/K-ATPase 是巨噬细胞 oxLDL-CD36 信号轴的关键组成部分。使用从 Atp1a1 杂合子或 Cd36 缺失小鼠中分离的腹膜巨噬细胞，我们证明 CD36 招募 Na/K-ATPase-Lyn 复合物以响应 oxLDL 激活 Lyn。缺乏 α1 Na/K-ATPase 催化亚基的巨噬细胞对 CD36 的激活没有反应，显示 oxLDL 摄取和泡沫细胞形成减弱，并且 oxLDL 无法抑制这些巨噬细胞的迁移。此外，作为动脉粥样硬化模型的 Apoe-null 小鼠，通过整体删除编码 α1 Na+/K+-ATPase 亚基的单个等位基因或用缺乏编码 α1 Na+/K+-ATPase 亚基的等位基因的巨噬细胞重建，可以防止饮食诱导的动脉粥样硬化。这些发现将 Na/K-ATPase 确定为预防或治疗抗动脉粥样硬化治疗的潜在靶点。
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 LDL (oxLDL) to the scavenger receptor CD36 activates the kinase Lyn, initiating a cascade that inhibits macrophage migration and is necessary for foam cell generation. Here, 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 a 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 anti-atherosclerotic therapy.