Promoting the transition from pyroptosis to apoptosis in endothelial cells: a novel approach to alleviate methylglyoxal-induced vascular damage

Background: Methylglyoxal (MGO)-induced cell death in vascular endothelial cells (VECs) plays a critical role in the progression of diabetic vascular complications (DVCs). Previous studies have shown that MGO can induce inflammatory pyroptosis, leading to VEC damage. However, the underlying mechanism remains unclear, and effective interventions are yet to be developed. Methods: Human umbilical vein endothelial cells (HUVECs) were used for in vitro experiments. Cell death modes were assessed through morphological observations. Mechanistic investigations were performed using immunofluorescence, flow cytometry, Western blotting, and ELISA. Inhibitors and adenoviruses were employed to validate the mechanisms. Vascular organoids in conjunction with AngioTool plug-in assays were used to evaluate VEC damage and angiogenic capacity. Mouse blood pressure was measured using the tail-cuff method, and vascular morphology was examined through hematoxylin and eosin (H&E) staining as well as immunofluorescence staining. Data were analyzed using the GraphPad Prism software. Results: Our study revealed that MGO induces pyroptosis in VECs via the Caspase3/gasdermin E (GSDME) pathway. Furthermore, the saponin monomer 13 of dwarf lilyturf tuber (DT-13), inhibited MGO-induced pyroptosis and promoted the generation of apoptotic bodies, facilitating the transition from pyroptosis to apoptosis. Mechanistically, DT-13 suppressed the Caspase3-mediated cleavage of GSDME and non-muscle myosin heavy chain IIA (NMMHC IIA), while increasing the phosphorylation of myosin light chain 2 (MLC2), which facilitated apoptotic body formation. Additionally, DT-13 was shown to mitigate VEC damage, inhibit angiogenesis, reduce vascular remodeling, and alleviate MGO-induced hypertension. Conclusions: This study uncovers a novel mechanism through which MGO induces VEC damage, highlighting the therapeutic significance of the transition from pyroptosis to apoptosis in this process. These findings suggest potential therapeutic strategies for managing diabetic angiopathy. Furthermore, DT-13 emerges as a promising compound for therapeutic intervention, offering new possibilities for clinical applications.