Mengge Yao, Kunchen Xu, Jiakang Li, Mao Dai, Rumei Xie, Wenjing Yi, Zhou Jie, Liangwan Chen, Li Zhang
The Key Laboratory of Fujian Province Universities on Ion Channel and Signal Transduction in Cardiovascular Diseases, Department of Physiology and pathophysiology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.; Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China.; Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, Fujian Province University, Fuzhou, China.; Hainan Women and Children's Medical Center, Haikou, China.
The Key Laboratory of Fujian Province Universities on Ion Channel and Signal Transduction in Cardiovascular Diseases, Department of Physiology and pathophysiology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Cell Signal. 2025 Jul 11;135:111986. doi: 10.1016/j.cellsig.2025.111986.
Inflammatory processes are closely associated with the pathogenesis of aortic dissection (AD). Pyroptosis, a caspase-dependent programmed cell death mechanism, plays a pivotal role in amplifying inflammatory cascades. High-mobility group box 2 (HMGB2), a pro-inflammatory mediator released by immune cells, has emerged as a critical regulator in cardiovascular pathologies. However, its specific involvement in AD development remains poorly characterized.
Ascending aortic specimens from AD patients were analyzed to evaluate HMGB2 expression and pyroptosis-related markers. An AD mouse model with aortic HMGB2 overexpression was established to assess histopathological progression. In vitro, human aortic vascular smooth muscle cells (HAVSMCs) were stimulated with angiotensin II (Ang II) to investigate pyroptosis dynamics following HMGB2 knockdown or overexpression. Mitochondrial parameters, including morphology, activity, membrane potential, and reactive oxygen species (ROS) generation, were systematically analyzed.
HMGB2 expression was significantly elevated in AD patient aortas, correlating with enhanced pyroptotic activity. HMGB2 overexpression exacerbated pyroptosis and accelerated AD progression in murine models. Mechanistically, HMGB2 silencing attenuated Ang II-induced pyroptosis in HAVSMCs by suppressing the Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling axis. Pharmacological inhibition of TLR4 effectively abrogated HMGB2-mediated pyroptotic activation. Furthermore, HMGB2 knockdown mitigated Ang II-triggered mitochondrial dysfunction, evidenced by restored membrane potential, reduced ROS overproduction, and preserved NADPH levels.
Our findings demonstrate that HMGB2 orchestrates pyroptosis in HAVSMCs through dual regulation of ROS generation and TLR4/NF-κB pathway activation. This study unveils HMGB2 as a novel molecular nexus linking oxidative stress, inflammation, and vascular cell death in AD pathogenesis, providing a conceptual framework for developing targeted diagnostic and therapeutic strategies.
炎症过程与主动脉夹层（AD）的发病机制密切相关。焦亡是一种半胱天冬酶依赖性程序性细胞死亡机制，在放大炎症级联反应中起关键作用。高迁移率族蛋白盒2（HMGB2）是免疫细胞释放的一种促炎介质，已成为心血管疾病的关键调节因子。然而，其在AD发展中的具体作用仍不清楚。
分析AD患者升主动脉标本，以评估HMGB2表达和焦亡相关标志物。建立主动脉HMGB2过表达的AD小鼠模型，以评估组织病理学进展。在体外，用人血管紧张素II（Ang II）刺激人主动脉血管平滑肌细胞（HAVSMCs），以研究HMGB2基因敲低或过表达后的焦亡动态。系统分析线粒体参数，包括形态、活性、膜电位和活性氧（ROS）生成。
AD患者主动脉中HMGB2表达显著升高，与焦亡活性增强相关。HMGB2过表达加剧了焦亡，并加速了小鼠模型中的AD进展。机制上，HMGB2沉默通过抑制Toll样受体4（TLR4）/核因子κB（NF-κB）信号轴减弱了Ang II诱导的HAVSMCs焦亡。TLR4的药理学抑制有效消除了HMGB2介导的焦亡激活。此外，HMGB2基因敲低减轻了Ang II引发的线粒体功能障碍，表现为膜电位恢复、ROS过度产生减少和NADPH水平保持。
我们的研究结果表明，HMGB2通过对ROS生成和TLR4/NF-κB途径激活的双重调节来协调HAVSMCs中的焦亡。本研究揭示了HMGB2是AD发病机制中连接氧化应激、炎症和血管细胞死亡的新型分子枢纽，为制定靶向诊断和治疗策略提供了概念框架。
