Alteration of volume-regulated chloride channel during macrophage-derived foam cell formation in atherosclerosis

Volume-regulated Cl(-) channel (VRCC) plays a critical role in regulation of a variety of physiological functions. However, little is known whether VRCC is involved in atherosclerosis. In this study, we investigated the functions of VRCC during foam cell formation in macrophages.

Treatment of RAW264.7 cells with ox-LDL increased intracellular cholesterol content as well as cell volume. After ox-LDL treatment, the resting [Cl(-)](i) in isotonic solution was decreased. Hypotonic solution reduced [Cl(-)](i) and evoked volume-regulated Cl(-) current in all the cells, however, the swelling-induced reduction of [Cl(-)](i) and increase of Cl(-) current were more prominent in ox-LDL treated cells than that in control. The increases of volume-regulated Cl(-) movement positively correlated with the intracellular cholesterol content. Moreover, in peritoneal macrophages isolated from high-fat diet ApoE(-/-) mice, the swelling-induced Cl(-) movement and current were enhanced compared with those in control group, and their increments positively correlated with atherosclerotic plaque area. Finally, activation of VRCC by hypotonic medium significantly accelerated, whereas, inhibition of VRCC with Cl(-) channel blockers remarkably attenuated, ox-LDL-induced macrophage-derived foam cell formation.

The activity of VRCC is augmented during macrophage-derived foam cell formation. Activation of VRCC accelerated, whereas, inhibition of VRCC attenuated, ox-LDL-induced lipid accumulation in macrophages, suggesting VRCC is involved in the regulation of foam cell formation.