Specific Kv1.3 blockade modulates key cholesterol-metabolism-associated molecules in human macrophages exposed to ox-LDL

Abstract

Atherosclerosis contributes chiefl y to ischemic diseases, including coronary heart disease, cerebral infarction, and intermittent claudication. Lipid plaque is the main pathological presentation and is characterized by abundant foam cells, which are derived mostly from macrophages. In the transformation, cholesterol ester accumulation accelerates foam cell formation.Macrophages possess an entrance-to-exit machinery for the modulation of cholesterol metabolism. Scavenger receptor class A (SR-A), CD36, and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) are largely responsible for cholesterol infl ux ( 1-8 ), and ABCA1, ABCG1 and scavenger receptor class B type I (SR-B I) facilitate cholesterol effl ux ( 9-15 ). Free cholesterol inside macrophages is esterifi ed by ACAT1, thereby promoting cholesterol ester accumulation ( 16-18 ). All the molecules form an integrated modulating 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 specifi c hKv1.3 blocker inhibited outward delayed rectifi er potassium currents, whereas the hKv1.5-E313 antibody that we had generated as a specifi c hKv1.5 blocker failed. Accordingly, the hKv1.3-E314 antibody reduced percentage of cholesterol ester and enhanced apoA-I-mediated cholesterol effl ux 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 specifi c Kv1.3 blockade represents a novel strategy modulating cholesterol metabolism in macrophages, which benefi ts the treatment of atherosclerotic lesions. Press, October 24, 2012 DOI 10.1194 Specifi c Kv1.3 blockade modulates key cholesterol-metabolism-associated molecules in human macrophages exposed to ox-LDL Published, JLR Papers in

Macrophage‐mediated cholesterol handling in atherosclerosis

“…Kv1.3 activation led to increased activity of SR‐A1 and enhanced uptake of oxLDL. Indeed, antibody‐dependent Kv1.3 blockade resulted in reduced oxLDL entrance, decreased cholesterol esterification and enhanced apoA‐I‐mediated cholesterol efflux . This finding may have important pharmaceutical consequences as it allows specific targeting and modulation of lipid accumulation in macrophages.…”

“…Insulin also up‐regulates ACAT1 expression in macrophages via extracellular signal‐regulated kinase (Erk)/p38MAP kinase/Jnk‐dependent activation of CCAAT/enhancer binding protein α, a transcriptional regulator . Except regulation of SR‐A1 activity, voltage‐gated potassium channel Kv1.3 is involved in the up‐regulation of ACAT1 that leads to enhanced uptake of oxLDL and accumulation of cholesterol ethers in macrophages .…”

“…Scavenger receptor‐BI is responsible for cholesterol transfer to HDL. The human receptor is encoded by the SCARB1 gene located on chromosome 12g24.31 . Two SR‐BI isoforms could be translated from the human SCARB1 gene.…”

Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance

“…ShK-186 treatment significantly reduced TNFα expression in visceral WAT (Fig. 2F), possibly via its known immunomodulatory effects on T cells and macrophages (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). The low uncoupling protein 1 (UCP1) Fig.…”

Kv1.3 channel blockade enhances the phagocytic function of RAW264.7 macrophages

“…Among these channels, the Kv channels play a pivotal role in the modulation of macrophage physiology [13]. For example, certain voltage-dependent K + channels, such as Kv1.3, Kv1.5, Kir2.1, and outward delayed rectifier K + channel, demonstrate differential responses during macrophage proliferation and activation [7]; the expression pattern of Kv subunit is dependent on the proliferation and activation mode in macrophages [14]; Kv1.3 and Kv1.5 co-associate and generate functional heterotetramers in macrophages [8]; selective Kv1.3 blockade affects the expression levels of some important cholesterol-metabolismassociated molecules (scavenger receptor class A, lectinlike oxidized low-density lipoprotein receptor-1, acetylcoenzyme A acetyltransferase 1 (ACAT1), and ATPbinding cassette transporter A1 (ABCA1)) in human macrophages exposed to ox-LDL [15]; Kv1.3 and Kv1.5 are involved in the induction of macrophage apoptosis [16]; and Kv1.3 modulates macrophage migration [17]. Kv1.3 channel is also involved in the maintenance of membrane potential, Ca 2+ signaling, proliferation, and activation of immune cells such as macrophages [18,19].…”