Preeclamptic plasma disrupts endothelial function and promotes inflammation in endothelial cells: beneficial effects of glibenclamide and MCC950 in this scenario

Preeclampsia (PE) is characterized by systemic endothelial dysfunction and remains a significant clinical challenge. Activation of NLRP3 inflammasome, reactive oxygen species (ROS) production, and pyroptosis and autophagy are important mechanisms in this condition. To evaluate the NLRP3 inhibitors effects: glibenclamide (GB) and MCC950, on markers of inflammation, endothelial dysfunction, cell death, and oxidative stress in an in vitro model of PE. Plasma from pregnant women with PE and normotensive pregnant women (NT) was used to investigate its impact on NLRP3 inflammasome activation (NLRP3, TLR4, MyD88, and caspase-1) in endothelial cells (ECs), analyzed by Western Blotting; effects of pharmacological inhibition on the function of ECs was assessed by the evaluation of permeability (VE-cadherin) and markers of endothelial dysfunction by flow cytometry (Flt-1, VEGFR2, E-selectin, VCAM-1, and ICAM-1), as well as cytotoxicity measured by lactate dehydrogenase (LDH), oxidative stress (ROS, nitric oxide - NO and antioxidant capacity), autophagy, and pyroptosis (interleukin IL-1β and high-mobility group box one - HMGB1). Both GB and MCC950 reduced NLRP3 inflammasome activation and its related effects in ECs exposed to PE plasma, including lowered IL-1β, caspase-1, modulated adhesion molecules expression, as well as decreased ROS and cytotoxicity. GB increased NO and restored VE-cadherin expression, while MCC950 enhanced antioxidant capacity. GB also induced autophagy, unlike MCC950. The NLRP3 inhibitors showed the potential to mitigate endothelial dysfunction, oxidative stress, and inflammation, suggesting both compounds hold potential therapeutic value for PE through distinct mechanisms.