451-P: Different Cardioprotective Efficacy of Metformin, Empagliflozin, and Semaglutide to Attenuate High Glucose–Oxidative Stress via Nrf2/Keap1 in Murine Cardiomyocytes

SGLT2 inhibitors (SGLT2is) and GLP-1R agonists (GLP-1RAs) represent the innovative drugs in the management of failure and ischemic heart disease. Moreover, new studies are evaluating metformin (M) action on heart. However, cardiac cellular mechanisms regulated by glucose-lowering drugs have yet to be adequately investigated. This study aimed to compare M, E and GLP-1RA semaglutide (S) impact on i) mitochondrial reactive oxygen species (mtROS) production, ii) Nrf2/Keap1 axis, and iii) cellular damages induced by high glucose in H9c2 rat cardiomyocytes. H9c2 were exposed to normal (NG, 5.5 mM) or high glucose (HG, 33 mM) for 48 h and treated with 400 uM M (MHG), 500 nM E (EHG) or 100 nM S (SHG) for 24 h. H9c2 cells were cultured in NG or HG as controls. E and S reduced HG-induced mtROS production whereas M action was ineffective. Consistent with these results, E and S significantly activated Nrf2/Keap1 axis promoting Nrf2 translocation into the nuclei and the anti-oxidant response. In MHG cells, Nrf2 translocation was limited. As known, Nrf2/Keap1 is modulated by AKT and AMPK pathways that are inhibited by HG. E significantly improved AMPK activation whereas S increased AKT signaling. M weakly rise AMPK activation. HG induced-mtROS is associated to ERKs up-activation and structural alterations. In HG medium, H9c2 became hypertrophic and acquired rounded morphology. Both E and S significantly downregulated ERKs activation and restored fusiform morphology and size. M only counteracted hypertrophic process. All drugs have a similar effect only on cellular viability rescuing the reduction of H9c2 proliferation caused by HG. Overall, our results suggest that i) E and S are more effective in mitigating HG-induced cardiac injury that M, ii) E and S seem act in similar manner, reducing mtROS via Nrf2/Keap1 axis, and restoring respectively AMPK and AKT signaling. This study suggests potential combined therapy in diabetic patients.