Colchicine Alleviates Cholesterol Crystal-Induced Endothelial Cell Pyroptosis through Activating AMPK/SIRT1 Pathway
Colchicine Alleviates Cholesterol Crystal-Induced Endothelial Cell Pyroptosis through Activating AMPK/SIRT1 Pathway
复制标题
秋水仙碱通过激活 AMPK/SIRT1 通路减轻胆固醇晶体诱导的内皮细胞焦亡
DOI：
10.1155/2020/9173530
复制
发表时间：
2020-07-15
影响因子：
--
通讯作者：
Yu, Bo
中科院分区：
文献类型：
--
作者：
Yang, Mengyue;Lv, Hang;Yu, Bo
胆固醇晶体（CC-）诱导的内皮细胞炎症和细胞凋亡在心血管疾病尤其是动脉粥样硬化（AS）的发生发展中起重要作用。越来越多的证据表明，胆固醇结晶是动脉粥样硬化斑块易损性的关键病理标志物。秋水仙碱作为一种经典的非特异性抗炎药，已广泛应用于急性痛风的治疗。然而，秋水仙碱是否能减轻CC诱导的内皮细胞损伤及其相关机制仍有待进一步研究。本研究证实了秋水仙碱对人脐静脉内皮细胞（HUVECs）的保护作用。结果显示，秋水仙素与胆固醇晶体共同作用后，内皮细胞对胆固醇晶体的摄取明显减少，细胞活力明显提高，乳酸脱氢酶（LDH）释放量和致炎细胞数明显减少，NLRP 3炎性体相关蛋白和多种炎症因子的表达也明显受到抑制;此外，作为NLRP 3炎性体的有效激活剂，细胞内ROS水平明显降低，而线粒体膜电位显著提高。此外，AMP依赖性激酶（AMPK）通路相关蛋白以及各种抗氧化酶的表达水平也不同程度地显著升高。然而，秋水仙碱的上述作用被靶向AMPKα和Sirtuin 1（SIRT 1）的siRNA处理完全抵消。因此，秋水仙碱通过调节AMPK/SIRT 1信号通路，在减轻细胞内炎症反应和NLRP 3炎症激活、减轻内皮细胞氧化应激和细胞凋亡中发挥重要作用，这可能是其对心血管疾病二级预防的具体机制。
Cholesterol crystal- (CC-) induced endothelial cell inflammation and pyroptosis play an important role in the development of cardiovascular diseases, especially in atherosclerosis (AS). Increasing evidence suggests that cholesterol crystals are known to be a pivotal pathological marker of atherosclerotic plaque vulnerability. As a classical nonspecific anti-inflammatory drug, colchicine has been widely used in the treatment of acute gout. However, whether colchicine could alleviate CC-induced endothelial cell injury and the related mechanisms remains to be addressed. In this study, the protective effect of colchicine on human umbilical vein endothelial cells (HUVECs) was confirmed. Our results revealed that after cotreatment with colchicine and cholesterol crystals in endothelial cells, the uptake of cholesterol crystals was significantly decreased, the cell viability was obviously increased, and the release of lactate dehydrogenase (LDH) and the number of pyroptotic cells decreased significantly; then, the expression of NLRP3 inflammasome-related proteins and various inflammatory factors was also visibly suppressed; moreover, as a potent activator of NLRP3 inflammasome, the intracellular ROS level was clearly reduced, while mitochondrial membrane potential improved significantly. In addition, the expression levels of AMP-dependent kinase (AMPK) pathway-related proteins as well as various antioxidant enzymes were elevated notably in varying degrees. However, the above effects of colchicine were completely offset by the treatment of siRNA targeting AMPKα and Sirtuin1 (SIRT1). Therefore, we conclude that colchicine plays a crucial role in alleviating the intracellular inflammatory response and NLRP3 inflammation activation, attenuating the levels of cellular oxidative stress and pyroptosis in endothelial cells via regulating AMPK/SIRT1 signaling, which may be a concrete mechanism for the secondary prevention of cardiovascular diseases.