title: Specific Kv1.3 blockade modulates key cholesterol-metabolism-associated molecules in human macrophages exposed to ox-LDL.
abstract: 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.
authors.affiliation: Department of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.forename: Yan-Fu
authors.initials: YF
authors.lastname: Wang
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yang
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Wang
authors.forename: Yi-Tian
authors.initials: YT
authors.lastname: Lian
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Yan-Wen
authors.initials: YW
authors.lastname: Shu
authors.forename: Long-Xian
authors.initials: LX
authors.lastname: Cheng
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Liao
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D000918:Antibody Specificity; D016632:Apolipoprotein A-I / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D011188:Potassium / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D051664:Kv1.3 Potassium Channel; D051666:Kv1.5 Potassium Channel; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D051117:Scavenger Receptors, Class A; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D002784:Cholesterol; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase; D011188:Potassium