Atherosclerosis still remains the leading cause of morbidity and mortality worldwide, and deeper understanding of target signaling that protect from the atherosclerosis progression may provide novel therapeutic strategies. CDGSH iron-sulfur domain-containing protein 1 (CISD1) is a protein localized on the outer membrane of mitochondria, and plays key roles in regulating cell death and oxidative stress. However, its potential on atherosclerosis development and the underlying mechanisms are largely unknown. Here, in our study, we found markedly decreased CISD1 expression in lipid-laden THP1 macrophages. Notably, lentivirus (LV)-mediated CISD1 over-expression remarkably ameliorated lipid deposition in macrophages stimulated by ox-LDL. Furthermore, cellular total ROS and mitochondrial ROS generation, and impairment of mitochondrial membrane potential (MMP) were highly induced by ox-LDL in THP1 cells, while being considerably reversed upon CISD1 over-expression. Inflammatory response caused by ox-LDL was also significantly restrained in macrophages with CISD1 over-expression. Mechanistically, we found that CISD1 could interact with dynamin-related protein 1 (Drp1). Intriguingly, CISD1-improved mitochondrial dysfunction and inflammation in ox-LDL-treated macrophages were strongly abolished by Drp1 over-expression, indicating that Drp1 suppression might be necessary for CISD1 to perform its protective effects in vitro. In high fat diet (HFD)-fed apolipoprotein E-deficient (ApoE^−/−) mice, tail vein injection of lentiviral vector expressing CISD1 remarkably decreased atherosclerotic lesion area, serum LDL cholesterol levels and triglyceride contents. Inflammatory response, cellular total and mitochondrial ROS production, and Drp1 expression levels in aorta tissues were also dramatically ameliorated in HFD-fed ApoE^−/− mice, contributing to the inhibition of atherosclerosis in vivo. Therefore, improving CISD1 expression may be a novel therapeutic strategy for atherosclerosis treatment.

动脉粥样硬化仍然是全世界发病率和死亡率的主要原因，深入了解防止动脉粥样硬化进展的靶标信号可能提供新的治疗策略。CDGSH 含铁硫域蛋白 1 (CISD1) 是一种定位于线粒体外膜的蛋白质，在调节细胞死亡和氧化应激中起关键作用。然而，其对动脉粥样硬化发展的潜力和潜在机制在很大程度上是未知的。在这里，在我们的研究中，我们发现富含脂质的 THP1 巨噬细胞中 CISD1 的表达显着降低。值得注意的是，慢病毒 (LV) 介导的 CISD1 过表达显着改善了 ox-LDL 刺激的巨噬细胞中的脂质沉积。此外，细胞总 ROS 和线粒体 ROS 的产生，THP1 细胞中的 ox-LDL 高度诱导线粒体膜电位 (MMP) 和损伤，而在 CISD1 过表达时显着逆转。在 CISD1 过表达的巨噬细胞中，ox-LDL 引起的炎症反应也受到显着抑制。从机制上讲，我们发现 CISD1 可以与动力蛋白相关蛋白 1 (Drp1) 相互作用。有趣的是，在 ox-LDL 处理的巨噬细胞中，CISD1 改善的线粒体功能障碍和炎症被 Drp1 过度表达强烈消除，表明 Drp1 抑制可能是 CISD1 发挥其保护作用所必需的 从机制上讲，我们发现 CISD1 可以与动力蛋白相关蛋白 1 (Drp1) 相互作用。有趣的是，在 ox-LDL 处理的巨噬细胞中，CISD1 改善的线粒体功能障碍和炎症被 Drp1 过度表达强烈消除，表明 Drp1 抑制可能是 CISD1 发挥其保护作用所必需的 从机制上讲，我们发现 CISD1 可以与动力蛋白相关蛋白 1 (Drp1) 相互作用。有趣的是，在 ox-LDL 处理的巨噬细胞中，CISD1 改善的线粒体功能障碍和炎症被 Drp1 过度表达强烈消除，表明 Drp1 抑制可能是 CISD1 发挥其保护作用所必需的体外。在高脂肪饮食 (HFD) 喂养的载脂蛋白 E 缺陷 (ApoE ^-/- ) 小鼠中，尾静脉注射表达 CISD1 的慢病毒载体显着降低了动脉粥样硬化病变面积、血清 LDL 胆固醇水平和甘油三酯含量。在喂食 HFD 的 ApoE ^-/-小鼠中，炎症反应、细胞总和线粒体 ROS 产生以及主动脉组织中的 Drp1 表达水平也显着改善，有助于抑制体内动脉粥样硬化。因此，提高CISD1的表达可能是动脉粥样硬化治疗的一种新的治疗策略。