Reduction of Intracellular Chloride Concentration Promotes Foam Cell Formation
Reduction of Intracellular Chloride Concentration Promotes Foam Cell Formation
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细胞内氯化物浓度的降低促进泡沫细胞形成
DOI：
10.1253/circj.cj-15-1209
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发表时间：
2016-04-01
影响因子：
3.3
通讯作者：
Liang, Si-Jia
中科院分区：
文献类型：
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作者：
Wu, Qian-Qian;Liu, Xiao-Yun;Liang, Si-Jia
背景：先前的研究表明，体积调节的氯离子通道在泡沫细胞形成过程中被激活，抑制氯离子的运动可以防止细胞内脂质积累。然而，氯离子运动促进泡沫细胞形成的机制尚不清楚。方法与结果：油红O染色法测定泡沫细胞形成。Western blotting和免疫共沉淀法检测蛋白表达和蛋白相互作用。[Cl-](i)用6-甲氧基- n -乙基碘化喹啉染料测定。结果表明，高胆固醇血症患者和高脂肪饮食喂养的apoE（-/-）小鼠的单核/巨噬细胞中[Cl-](i)减少。降低[Cl-](i)上调清清剂受体A （SR-A）的表达，增加oxLDL的结合和摄取，增强促炎细胞因子的产生，随后加速人和小鼠巨噬细胞泡沫细胞的形成。此外，低cl溶液刺激了JNK和p38丝裂原活化蛋白激酶的激活。JNK和p38的抑制阻断了cl减少的培养基诱导的SR-A表达和脂质积累。相反，[Cl-](i)的减少促进了SR-A与caveolin-1的相互作用，从而促进了caveolin-1依赖性SR-A的内吞作用。此外，小泡的破坏减弱了SR-A的内化、JNK和p38的激活，最终阻止了低cl介质刺激下SR-A的表达和泡沫细胞的形成。结论：这些数据提供了强有力的证据，表明[Cl-](i)的减少是细胞内脂质积累的关键因素，表明[Cl-](i)的调节是防止泡沫细胞形成和动脉粥样硬化的新途径。
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.