Reduction of Intracellular Chloride Concentration Promotes Foam Cell Formation

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Background:Previous work has demonstrated that the volume-regulated chloride channel is activated during foam cell formation, and inhibition of chloride movement prevents intracellular lipid accumulation. However, the mechanism explaining how chloride movement promotes foam cell formation is not clear.Methods and Results:Foam cell formation was determined by Oil Red O staining. Western blotting and co-immunoprecipitation were used to examine protein expression and protein-protein interaction. [Cl⁻]_iwas measured using 6-methoxy-N-ethylquinolinium iodide dye. The results showed that [Cl⁻]_iwas decreased in monocytes/macrophages from patients with hypercholesterolemia and from apoE^−/−mice fed with a high-fat diet. Lowering [Cl⁻]_iupregulated scavenger receptor A (SR-A) expression, increased the binding and uptake of oxLDL, enhanced pro-inflammatory cytokine production and subsequently accelerated foam cell formation in macrophages from humans and mice. In addition, low Cl⁻solution stimulated the activation of JNK and p38 mitogen-activated protein kinases. Inhibition of JNK and p38 blocked Cl⁻reduced medium-induced SR-A expression and lipid accumulation. In contrast, reduction of [Cl⁻]_ipromoted the interaction of SR-A with caveolin-1, thus facilitating caveolin-1-dependent SR-A endocytosis. Moreover, disruption of caveolae attenuated SR-A internalization, JNK and p38 activation, and ultimately prevented SR-A expression and foam cell formation stimulated by low Cl⁻medium.Conclusions:This data provide strong evidence that reduction of [Cl⁻]_iis a critical contributor to intracellular lipid accumulation, suggesting that modulation of [Cl⁻]_iis a novel avenue to prevent foam cell formation and atherosclerosis.