Introduction: Chronic inflammation and mitochondrial dysfunction are key drivers of endothelial aging and cardiovascular diseases. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are known for their cardiovascular protective effects. However, the underlying molecular mechanisms, especially their impact on autophagy and mitochondrial function, remain unclear. This study aims to investigate the effects of SGLT2 inhibitors on mitochondrial function and autophagy in endothelial cells.
Methods: Human endothelial cells derived from induced pluripotent stem cells (iPS-ECs) (n = 12) were activated with 10 ng/ml TNF-α for 24 hours to create a pro-inflammatory environment and were then treated with 1 µM Empagliflozin for an additional 24 hours. Western blot analyses were performed to assess the expression and activity of key mitochondrial and autophagy markers, e.g., AMPK activity, SOD2 expression and autophagy flux.
Results: Pro-inflammatory treatment with TNF-α resulted in mitochondrial dysfunction and a disruption of autophagy. AMPK, a key cellular energy sensor and regulator of mitochondrial homeostasis, showed no significant differences in pAMPK/AMPK ratios among the investigated groups. SOD2, an anti-oxidative enzyme critical for mitochondrial antioxidant defense, exhibited lower expression in TNF-α-treated cells compared to untreated cells. Empagliflozin treatment partially recovered the expression of SOD2. Conversely, the autophagy flux (LC3II/I ratio) was elevated after pro-inflammatory treatment but subsequently decreased following Empagliflozin treatment.
Conclusion: Empagliflozin exhibits protective effects on endothelial inflammation by modulating mitochondrial function and autophagy activity. While Empagliflozin partially restored SOD2 expression, the AMPK activity was not changed. Additionally, SGLT2 inhibition recovered the autophagy flux to the basal levels, suggesting a regulatory effect of Empagliflozin on autophagy. These findings indicate that SGLT2 inhibitors may play a role in mitigating inflammation-induced mitochondrial dysfunction and autophagy disruption, offering potential therapeutic benefits for endothelial aging and cardiovascular diseases.
