Ma Meng-Qing, Yang Chun, Jin Shi-Yu, Yang Yu, Pan Yan-Yan, Lin Xian-He
Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.
Department of Cardiology, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui 230022, P.R. China.
Mol Med Rep. 2025 Jul;32(1). doi: 10.3892/mmr.2025.13551. Epub 2025 May 2.
Atherosclerosis (AS)‑related coronary artery disease is the main cause of morbidity and mortality around the globe. Eburicoic acid, a triterpenoid compound from , exerts anti‑inflammatory and anti‑hyperlipidemic effects, although its role in atherogenesis remains unknown. Endothelial cell pyroptosis‑caused chronic inflammatory response within vessel walls is a critical initial event in atherogenesis, making it a promising target to prevent AS. The present study was designed to investigate the effects of eburicoic acid on endothelial cell pyroptosis, AS progression and the underlying mechanisms. The results showed that with dose and time increased, treatment of human umbilical vascular endothelial cells (HUVECs) with eburicoic acid markedly decreased the expression of Kelch‑like ECH‑associated protein 1 (Keap1), NF‑E2‑related factor 2 (Nrf2), reactive oxygen species (ROS), NLR family pyrin domain‑containing protein 3 (NLRP3), cleaved caspase‑1, apoptosis‑associated speck‑like protein containing CARD (ASC), N‑terminal gasdermin‑D (GSDMD‑N), downregulated the secretion levels of pro‑inflammatory cytokines interleukin (IL) 1β, IL‑6 and IL‑18, inhibited caspase‑1 activity and lactate dehydrogenase release and improved plasma membrane integrity. By contrast, the expression of nuclear Nrf2, total Nrf2 and heme oxygenase‑1 (HO‑1) were increased by eburicoic acid treatment in HUVECs dose‑ and time‑dependently. Moreover, the inhibitory effects of eburicoic acid on HUVEC pyroptosis were mainly compromised by pre‑treatment with ROS agonist, HO‑1 small interfering (si)RNA, or Nrf2 siRNA. Finally, it was observed that administering high‑fat‑diet fed ApoE‑/‑ mice with eburicoic acid markedly increased Nrf2 and HO‑1 levels and reduced the expression of Keap1, NLRP3, cleaved caspase‑1, ASC and GSDMD‑N in aortas and ameliorated hyperlipidemia and inflammation in the serum, leading to smaller atherosclerotic plaques, less lipid accumulation and high content of collagen fiber within plaques. These findings identified eburicoic acid as a potent anti‑atherogenic natural product by suppressing endothelial cell pyroptosis via the Keap1/Nrf2/HO‑1/ROS pathway. Eburicoic acid may be considered an effective phytomedicine for treating AS.
动脉粥样硬化（AS）相关的冠状动脉疾病是全球发病和死亡的主要原因。来自[具体来源未提及]的三萜类化合物桦木酸具有抗炎和降血脂作用，但其在动脉粥样硬化发生中的作用尚不清楚。血管壁内由内皮细胞焦亡引起的慢性炎症反应是动脉粥样硬化发生的关键初始事件，使其成为预防AS的一个有前景的靶点。本研究旨在探讨桦木酸对内皮细胞焦亡、AS进展及其潜在机制的影响。结果表明，随着剂量和时间的增加，用桦木酸处理人脐静脉血管内皮细胞（HUVECs）可显著降低Kelch样ECH相关蛋白1（Keap1）、NF-E2相关因子2（Nrf2）、活性氧（ROS）、NLR家族含pyrin结构域蛋白3（NLRP3）、裂解的半胱天冬酶-1、含CARD的凋亡相关斑点样蛋白（ASC）、N端gasdermin-D（GSDMD-N）的表达，下调促炎细胞因子白细胞介素（IL）1β、IL-6和IL-18的分泌水平，抑制半胱天冬酶-1活性和乳酸脱氢酶释放，并改善质膜完整性。相比之下，在HUVECs中，桦木酸处理剂量和时间依赖性地增加了核Nrf2、总Nrf2和血红素加氧酶-1（HO-1）的表达。此外，ROS激动剂、HO-1小干扰（si）RNA或Nrf2 siRNA预处理主要削弱了桦木酸对HUVEC焦亡的抑制作用。最后，观察到给高脂饮食喂养的ApoE-/-小鼠施用桦木酸可显著提高主动脉中Nrf2和HO-1水平，降低Keap1、NLRP3、裂解的半胱天冬酶-1、ASC和GSDMD-N的表达，并改善血清中的高脂血症和炎症，导致动脉粥样硬化斑块更小、脂质积累更少且斑块内胶原纤维含量更高。这些发现确定桦木酸是一种有效的抗动脉粥样硬化天然产物，通过Keap1/Nrf2/HO-1/ROS途径抑制内皮细胞焦亡。桦木酸可被认为是一种治疗AS的有效植物药。
