Lv Zhen-Huan, Phuong Trinh Anh, Jin Shi-Jie, Li Xiao-Xue, Xu Ming
Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 311400, China.
Oncotarget. 2017 Aug 24;8(53):91291-91305. doi: 10.18632/oncotarget.20443. eCollection 2017 Oct 31.
Recent studies have demonstrated that NLRP3 inflammasome complex acts as pivotal elements to initiate inflammatory responses and plays an important role in the dysfunction of cardiovascular complications. Meanwhile, simvastatin prevents vascular endothelial dysfunction from inflammasome invasion contributing to reduce cardiovascular risk. However, Whether or not the simvastatin improves vascular endothelial barrier function through inhibiting the activation of NLRP3 inflammasome pathway remains unknown. Here, we explored the role and mechanisms of simvastatin in the activation of NLRP3 inflammasome which are involved in vascular endothelial hyperpermeability causing by the disruption of tight junction protein ZO-1 and adherens junction protein VE-Cadherin, an early initiation of cardiovascular complication. Our results found that high glucose significantly induced the formation and activation of NLRP3 inflammasome through NADPH oxidase-dependent reactive oxygen species (ROS) formation, associated with vascular endothelial hyperpermeability causing by ZO-1 and VE-Cadherin disruption in the rat aortic endothelial cells (RAECs). Simvastatin treatment remarkably abolished vascular endothelial hyperpermeability and enhanced the protein expression of ZO-1 and VE-Cadherin through NLRP3 inflammasome. Mechanistically, the inhibitory role of simvastatin endothelial hyperpermeability is attributed to the decreased release of cytoplasmic high mobility group box protein-1 (HMGB1) derived from endothelial NLRP3 inflammasome activation. We further confirm the protective role of simvastatin on vascular leakage in the heart of diabetic rats injected with Evans blue dye, which was associated with HMGB1 release in the serum. Collectively, the mechanism of simvastatin treatment alleviating vascular endothelial permeability dysfunction may be through inhibiting the NLRP3 inflammasome-dependent HMGB1 release in RAECs.
最近的研究表明，NLRP3炎性小体复合物是启动炎症反应的关键因素，在心血管并发症的功能障碍中起重要作用。同时，辛伐他汀可防止炎性小体侵袭导致的血管内皮功能障碍，有助于降低心血管风险。然而，辛伐他汀是否通过抑制NLRP3炎性小体途径的激活来改善血管内皮屏障功能仍不清楚。在此，我们探讨了辛伐他汀在NLRP3炎性小体激活中的作用和机制，该激活参与了由紧密连接蛋白ZO-1和黏附连接蛋白VE-钙黏蛋白破坏引起的血管内皮高通透性，这是心血管并发症的早期起始。我们的结果发现，高糖通过NADPH氧化酶依赖性活性氧（ROS）形成显著诱导NLRP3炎性小体的形成和激活，这与大鼠主动脉内皮细胞（RAECs）中ZO-1和VE-钙黏蛋白破坏导致的血管内皮高通透性有关。辛伐他汀治疗显著消除了血管内皮高通透性，并通过NLRP3炎性小体增强了ZO-1和VE-钙黏蛋白的蛋白表达。从机制上讲，辛伐他汀对内皮高通透性的抑制作用归因于内皮NLRP3炎性小体激活衍生的细胞质高迁移率族蛋白B1（HMGB1）释放减少。我们进一步证实了辛伐他汀对注射伊文思蓝染料的糖尿病大鼠心脏血管渗漏的保护作用，这与血清中HMGB1释放有关。总体而言，辛伐他汀治疗减轻血管内皮通透性功能障碍的机制可能是通过抑制RAECs中NLRP3炎性小体依赖性HMGB1释放。
