HMGB2 regulates pyroptosis of smooth muscle cells in aortic dissection by modulating ROS-TLR4-NF-κB pathway.

Background And Aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.