Inflamm Res. 2026 Sep 14;75(1):211. doi: 10.1007/s00011-026-02361-z.
ABSTRACT
RATIONALE: Atherosclerosis (AS) is a chronic inflammatory disease of the arterial walls, initiated by endothelial dysfunction and subendothelial lipid deposition. Even though treatments to lower lipids have improved, there are still not many options that specifically tackle inflammation-caused endothelial dysfunction in the early stage of AS. Spironolactone (SP) has been shown to be beneficial in reducing cardiovascular complications, and while it acts as a pharmacological inhibitor of pannexin 1 (Panx 1), the mechanism by which SP modulates Panx 1 in endothelial cells (ECs) during inflammation remains unclear.
OBJECTIVE: To identify Panx 1 on ECs is a key mediator through which SP ameliorates vascular inflammation, lowers oleic acid (OA)-induced intracellular neutral lipid accumulation, and sustains the function of ECs, thereby attenuating early AS.
METHODS AND RESULTS: In vivo, SP administration significantly ameliorated plasma biochemical parameters, mitigate aortic inflammation and reduced lipid deposition, thereby reducing endothelial activation and alleviating endothelium damage in an early AS model established by feeding ApoE-/- mice a high-fat diet. Non-targeted metabolomic profiling revealed that SP profoundly remodeled the plasma metabolome, indicating systemic metabolic restoration. In vitro, SP reversed TNF-α induced activation of ECs and attenuated OA-induced neutral lipid accumulation in human umbilical vein ECs. However, no significant difference of Panx 1 expression in ECs was observed between normal and abnormal endothelial function in AS mouse models or clinical subjects. Mechanistically, SP targeted Panx 1 as a pivotal mediator of the inflammatory response, not only inhibiting TNF-α induced Panx 1 expression but also significantly blocking the functional opening of Panx 1 channels, thereby preventing subsequent Ca2+ influx. This attenuation of intracellular Ca2+ overload was essential for the protective effects of SP against both endothelial dysfunction and inflammation-mediated OA to induce intracellular neutral lipid accumulation. Furthermore, we demonstrated that SP suppresses NFκB signaling activation by inhibiting the Panx 1-dependent intracellular Ca2+ rise, revealing a mechanistic Panx 1/Ca2+/NFκB axis that regulates inflammation-driven intracellular neutral lipid accumulation.
CONCLUSION: Taken together, these findings indicate that SP mitigates early AS by reduced endothelial activation and attenuating inflammation-driven intracellular neutral lipid accumulation via suppression of the Panx 1/Ca2+/NFκB signaling axis. This study establishes Panx 1 as a promising therapeutic target for early vascular intervention in AS and considers SP as a potential candidate for prevention of atherosclerotic cardiovascular disease.
PMID:42734843 | DOI:10.1007/s00011-026-02361-z