期刊
CIRCULATION JOURNAL
卷 80, 期 4, 页码 1024-+出版社
JAPANESE CIRCULATION SOC
DOI: 10.1253/circj.CJ-15-1209
关键词
Caveolin-1; Chloride; Foam cell formation; Scavenger receptor A (SR-A)
资金
- National Natural Science Foundation of China [81525025, 81473206, 81471132, 81273500, 81230082]
- Natural Science Foundation of Guangdong Province [2013010015263, 2014A030313030, 2014A030310031]
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-](i) was measured using 6-methoxy-N-ethylquinolinium iodide dye. The results showed that [Cl-](i) was decreased in monocytes/macrophages from patients with hypercholesterolemia and from apoE(-/-) mice fed with a high-fat diet. Lowering [Cl-](i) upregulated scavenger receptor A (SR-A) expression, increased the binding and uptake of oxLDL, enhanced proinflammatory 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-](i) promoted 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-](i) is a critical contributor to intracellular lipid accumulation, suggesting that modulation of [Cl-](i) is a novel avenue to prevent foam cell formation and atherosclerosis.
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