Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability
Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability
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KCa3.1通道在巨噬细胞极化中的作用及其与动脉粥样硬化斑块不稳定性的关系
DOI：
10.1161/atvbaha.116.308461
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发表时间：
2017-02-01
影响因子：
8.7
通讯作者：
Ge, Junbo
中科院分区：
文献类型：
--
作者：
Xu, Rende;Li, Chenguang;Ge, Junbo
新出现的证据表明，促炎性巨噬细胞极化失衡在动脉粥样硬化斑块的进展和不稳定性中起关键作用。钙激活钾通道KCa3.1与巨噬细胞的活化和功能密切相关。然而，KCa 3.1在巨噬细胞极化中的作用尚不清楚。本研究探讨KCa3.1在巨噬细胞极化及其与斑块不稳定性的关系中的转录调控的潜在作用。方法和结果-人单核细胞分化成巨噬细胞使用巨噬细胞集落刺激因子。巨噬细胞然后被干扰素极化为促炎性M1细胞。和脂多糖，并通过白细胞介素-4进入交替的M2巨噬细胞。通过联合部分结扎载脂蛋白E基因敲除小鼠的左肾动脉和左颈总动脉来诱导斑块不稳定性模型。在人单核细胞分化为巨噬细胞的过程中，观察到KCa 3.1表达的显著上调。阻断KCa3.1可显著降低巨噬细胞极化过程中促炎基因的表达。进一步的机制研究表明，阻断KCa3.1通过下调信号转导和转录激活因子-1磷酸化抑制巨噬细胞向M1表型分化。在动物模型中，KCa 3.1阻断治疗显著降低颈动脉斑块破裂和管腔血栓的发生率，降低与M1巨噬细胞极化相关的标志物的表达，并增强了动脉粥样硬化病变内M2标志物的表达。这些结果表明，阻断KCa3.1通过抑制巨噬细胞向M1的极化来抑制动脉粥样硬化晚期斑块的不稳定性表型
Objective-Emerging evidence indicates that proinflammatory macrophage polarization imbalance plays a key role in atherosclerotic plaque progression and instability. The calcium-activated potassium channel KCa3.1 is critically involved in macrophage activation and function. However, the role of KCa3.1 in macrophage polarization is unknown. This study investigates the potential role of KCa3.1 in transcriptional regulation in macrophage polarization and its relationship to plaque instability.Approach and Results-Human monocytes were differentiated into macrophages using macrophage colony-stimulating factor. Macrophages were then polarized into proinflammatory M1 cells by interferon-. and lipopolysaccharide and into alternative M2 macrophages by interleukin-4. A model for plaque instability was induced by combined partial ligation of the left renal artery and left common carotid artery in apolipoprotein E knockout mice. Significant upregulation of KCa3.1 expression was observed during the differentiation of human monocytes into macrophages. Blocking KCa3.1 significantly reduced the expression of proinflammatory genes during macrophages polarization. Further mechanistic studies indicated that blocking KCa3.1 inhibited macrophage differentiation toward the M1 phenotype by downregulating signal transducer and activator of transcription-1 phosphorylation. In animal models, KCa3.1 blockade therapy strikingly reduced the incidence of plaque rupture and luminal thrombus in carotid arteries, decreased the expression of markers associated with M1 macrophage polarization, and enhanced the expression of M2 markers within atherosclerotic lesions.Conclusions-These results suggest that blocking KCa3.1 suppresses plaque instability in advanced stages of atherosclerosis by inhibiting macrophage polarization toward an M1 phenotype.