State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Department of Respiratory Medicine, Kunming Children's Hosiptal, Kunming, China.
Drug Dev Res. 2019 Jun;80(4):481-489. doi: 10.1002/ddr.21521. Epub 2019 Feb 14.
Atherosclerosis (AS) is one of important events involving in the pathological process of coronary artery disease. Many traditional Chinese medicines have been widely used for the treatment of AS. Previous studies have demonstrated that Ilexgenin A (IA) obtained from Ilex hainanensis Merr. could improve AS development. However, its underlying mechanism is still unknown. This study was conducted to explore the possible targets and mechanisms involving in the anti-atheroclerosis effect of IA. The results showed IA significantly promoted NO production, reduced reactive oxygen species (ROS) generation, and inflammatory cytokine production induced by palmitate (PA) in endothelial cells, demonstrating IA could improve endothelial dysfunction. Meanwhile, IA dramatically inhibited dynamin-related protein 1 (Drp1) expression and mitochondrial fission induced by PA whereas proteasome inhibitor epoxomicin attenuated its effect on Drp1 expression, indicating IA decreased Drp1 expression with regulation of proteasome. Furthermore, IA also could increase the expression of proteasome subunit beta type5 (PSMB5) and activate nuclear factor-like 2 (Nrf2). Nrf2 knockdown eliminated the induction effect of IA on PSMB5 expression while abrogated its inhibition on ROS generation and mitochondrial fission stimulated by PA. These results demonstrated that IA could promote PSMB5 expression in an Nrf2-dependent manner, resulting in the suppression of mitochondrial fission, and thus improve endothelial dysfunction. These findings laid a foundation to the future development of IA as an agent to the prevention and treatment of AS.
动脉粥样硬化（AS）是涉及冠状动脉疾病病理过程的重要事件之一。许多中药已被广泛用于 AS 的治疗。先前的研究表明，从海南冬青中获得的冬青苷 A（IA）可以改善 AS 的发展。然而，其潜在机制尚不清楚。本研究旨在探讨 IA 抗动脉粥样硬化作用的可能靶点和机制。结果表明，IA 可显著促进棕榈酸（PA）诱导的内皮细胞中 NO 的产生，减少活性氧（ROS）的产生和炎性细胞因子的产生，表明 IA 可改善内皮功能障碍。同时，IA 可显著抑制 PA 诱导的动力相关蛋白 1（Drp1）表达和线粒体分裂，而蛋白酶体抑制剂环氧米酮可减弱其对 Drp1 表达的影响，表明 IA 通过调节蛋白酶体降低 Drp1 的表达。此外，IA 还可以增加蛋白酶体亚基β型 5（PSMB5）的表达并激活核因子样 2（Nrf2）。Nrf2 敲低消除了 IA 对 PSMB5 表达的诱导作用，同时消除了其对 PA 刺激的 ROS 生成和线粒体分裂的抑制作用。这些结果表明，IA 可以以 Nrf2 依赖的方式促进 PSMB5 的表达，从而抑制线粒体分裂，进而改善内皮功能障碍。这些发现为 IA 作为预防和治疗 AS 的药物的未来发展奠定了基础。
