Department of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
J Lipid Res. 2013 Jan;54(1):34-43. doi: 10.1194/jlr.M023846. Epub 2012 Oct 24.
Cholesterol-metabolism-associated molecules, including scavenger receptor class A (SR-A), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), CD36, ACAT1, ABCA1, ABCG1, and scavenger receptor class B type I, can modulate cholesterol metabolism in the transformation from macrophages to foam cells. Voltage-gated potassium channel Kv1.3 has increasingly been demonstrated to play an important role in the modulation of macrophage function. Here, we investigate the role of Kv1.3 in modulating cholesterol-metabolism-associated molecules in human acute monocytic leukemia cell-derived macrophages (THP-1 macrophages) and human monocyte-derived macrophages exposed to oxidized LDL (ox-LDL). Human Kv1.3 and Kv1.5 channels (hKv1.3 and hKv1.5) are expressed in macrophages and form a heteromultimeric channel. The hKv1.3-E314 antibody that we had generated as a specific hKv1.3 blocker inhibited outward delayed rectifier potassium currents, whereas the hKv1.5-E313 antibody that we had generated as a specific hKv1.5 blocker failed. Accordingly, the hKv1.3-E314 antibody reduced percentage of cholesterol ester and enhanced apoA-I-mediated cholesterol efflux in THP-1 macrophages and human monocyte-derived macrophages exposed to ox-LDL. The hKv1.3-E314 antibody downregulated SR-A, LOX-1, and ACAT1 expression and upregulated ABCA1 expression in THP-1 macrophages and human monocyte-derived macrophages. Our results reveal that specific Kv1.3 blockade represents a novel strategy modulating cholesterol metabolism in macrophages, which benefits the treatment of atherosclerotic lesions.
胆固醇代谢相关分子，包括清道夫受体 A 类（SR-A）、凝集素样氧化型低密度脂蛋白受体-1（LOX-1）、CD36、ACAT1、ABCA1、ABCG1 和清道夫受体 B 类 I 型，可调节巨噬细胞向泡沫细胞转化过程中的胆固醇代谢。电压门控钾通道 Kv1.3 越来越多地被证明在调节巨噬细胞功能方面发挥着重要作用。在这里，我们研究了 Kv1.3 在调节人急性单核细胞白血病细胞衍生的巨噬细胞（THP-1 巨噬细胞）和人单核细胞衍生的巨噬细胞中胆固醇代谢相关分子方面的作用，这些巨噬细胞暴露于氧化型低密度脂蛋白（ox-LDL）中。人 Kv1.3 和 Kv1.5 通道（hKv1.3 和 hKv1.5）在巨噬细胞中表达并形成异源多聚体通道。我们生成的特异性 hKv1.3 阻断剂 hKv1.3-E314 抗体抑制外向延迟整流钾电流，而我们生成的特异性 hKv1.5 阻断剂 hKv1.5-E313 抗体则不能。因此，hKv1.3-E314 抗体降低了胆固醇酯的百分比，并增强了 THP-1 巨噬细胞和暴露于 ox-LDL 的人单核细胞衍生巨噬细胞中载脂蛋白 A-I 介导的胆固醇流出。hKv1.3-E314 抗体下调了 THP-1 巨噬细胞和人单核细胞衍生巨噬细胞中 SR-A、LOX-1 和 ACAT1 的表达，上调了 ABCA1 的表达。我们的结果表明，特异性 Kv1.3 阻断代表了一种调节巨噬细胞中胆固醇代谢的新策略，有利于治疗动脉粥样硬化病变。
