Empagliflozin Improves Atherosclerosis by Promoting Mitophagy in Endothelial Cells
Abstract
Purpose: To investigate whether empagliflozin (EMPA) delays the progression of atherosclerosis (AS) by promoting mitophagy in endothelial cells.
Methods: In vivo and in vitro AS models were established using ApoE-/- mice fed a high-fat diet (HFD) and HUVECs treated with oxLDL, respectively. Models received EMPA intervention alone or combined with the autophagy inhibitor 3-MA. To specifically confirm the pivotal role of Pink1, siRNA-mediated knockdown was performed in HUVECs. Aortic plaque area was evaluated by Oil Red O staining. Serum lipids, mitochondrial function, and endothelial markers were assessed. Mitophagy-related proteins were detected by Western blot, and the co-localization of TOM20 with LC3 and CD31 with LC3 was observed via immunofluorescence.
Results: EMPA significantly reduced aortic plaque area and ameliorated lipid metabolism in mice, independent of hypoglycemic effects. In vitro, EMPA restored mitochondrial membrane potential and ATP levels while reducing ROS production. Furthermore, EMPA upregulated Pink1/Parkin expression and the LC3-II/LC3-I ratio, and promoted TOM20-LC3 co-localization. Critically, both 3-MA treatment and Pink1 knockdown reversed EMPA-induced improvements in endothelial viability and migration, abolished its inhibition of inflammatory cytokine release, and negated its regulatory effects on endothelial function, demonstrating that mitophagy is essential for EMPA's action.
Conclusion: EMPA inhibits the progression of AS by activating…
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