Targeting the KCa3.1 channel suppresses diabetes-associated atherosclerosis via the STAT3/CD36 axis
Targeting the KCa3.1 channel suppresses diabetes-associated atherosclerosis via the STAT3/CD36 axis
复制标题
靶向 KCa3.1 通道通过 STAT3/CD36 轴抑制糖尿病相关的动脉粥样硬化
DOI：
10.1016/j.diabres.2022.109776
复制
发表时间：
2022
影响因子：
5.1
通讯作者：
Dai-Min Zhang
中科院分区：
文献类型：
--
作者：
Xiao-Xin Jiang;Weikang Bian;Yan-Rong Zhu;Zhicheng Wang;Peng Ye;Yue Gu;Hongsong Zhang;Guangfeng Zuo;Xiaobo Li;Linlin Zhu;Zhizhong Liu;Chongxiu Sun;Shao-Liang Chen;Dai-Min Zhang
在饮食诱导的动脉粥样硬化中，KCa 3.1通道增加与动脉粥样硬化斑块的进展和不稳定性相关。巨噬细胞参与动脉粥样硬化斑块的形成，炎性细胞因子和氧自由基的释放促进斑块进展。然而，巨噬细胞KCa3.1通道是否促进糖尿病加速的动脉粥样硬化仍不清楚。方法和结果在体内，阻断KCa3.1通道可抑制高脂饮食的糖尿病ApoE-/-小鼠动脉粥样硬化病变的发展，在体外，HG + ox-LDL处理的RAW264.7细胞中KCa3.1通道水平呈时间依赖性上调。阻断KCa 3.1可显著降低小鼠腹腔巨噬细胞对ox-LDL的摄取。结论阻断巨噬细胞KCa3.1通道可通过抑制STAT 3/CD 36轴抑制细胞内氧化型低密度脂蛋白（OLDL）的积累，降低促炎因子的表达。本研究为降低糖尿病患者动脉粥样硬化的风险提供了一个新的治疗靶点。
BackgroundIn diet-induced arterial atherosclerosis, increased KCa3.1 channel was associated with atherosclerotic plaque progression and instability. Macrophages are involved in the formation of atherosclerotic plaques, and the release of inflammatory cytokines and oxygen free radicals promotes plaque progression. However, whether the macrophage KCa3.1 channel facilitates diabetes-accelerated atherosclerosis is still unclear. This study investigated atherosclerotic plaque in ApoE-/-mice regulated by the KCa3.1 channel.Methods and ResultsIn vivo, blocking KCa3.1channel inhibit the development of the atherosclerotic lesion in diabetic ApoE-/-mice fed with a high-fat diet.In vitro, upregulation of KCa3.1 channel level occurred in RAW264.7 cells treated with HG plus ox-LDL in a time-dependent manner. Blocking KCa3.1 significantly reduced the uptake of ox-LDL in mice peritoneal macrophages. Further studies indicated the KCa3.1 siRNA and TRAM-34 (KCa3.1 inhibitor) attenuated the scavenger receptor CD36 expression via inhibiting STAT3 phosphorylation.ConclusionBlockade of macrophage KCa3.1 channel inhibit cellular oxidized low-density lipoprotein accumulation and decrease proinflammation factors expression via STAT3/CD36 axis. This study provided a novel therapeutic target to reduce the risk of atherosclerosis development in diabetic patients.