Investigating the effects of empagliflozin on myocardial metabolic and lipid profile in healthy and metabolic syndrome murine models following acute myocardial infarction

Abstract Background/Introduction Empagliflozin (EMPA) is a sodium/glucose co-transporter type 2 inhibitor with clinically documented cardioprotective effect. However, the mechanism of cardioprotection remains elusive. We have previously shown that Western diet induces metabolic syndrome (MS) and deteriorates cardiac function in mice, whereas EMPA treatment for 6 weeks prevents this damage. Also, EMPA administration for 6 weeks suppresses ischemia/reperfusion (I/R) injury in mice, independent of the presence of MS. Purpose The aim of the present study is to investigate whether changes in myocardial metabolic and lipid profile, induced by EMPA treatment, are responsible for its cardioprotective effect in the setting of myocardial I/R injury. Methods C57Bl6 mice received chow diet or Western diet for 14 weeks. At week 8, mice from each dietary group were randomized into 3 subgroups: 1. Control - Sham surgery (5% DMSO-SHAM), 2. Control - I/R (5% DMSO-I/R) and 3. EMPA (10mg/kg/day in 5% DMSO) - I/R (EMPA-I/R) and received the corresponding treatment by daily per os administration for 6 weeks. At week 14, mice were subjected to 30 minutes of I, followed by 2 hours of R, or sham surgery. Myocardial tissue was harvested at the end of R, and metabolomic and lipidomic analysis was performed by nuclear magnetic resonance spectroscopy and mass spectrometry, respectively. Body weight, as well as blood glucose and cholesterol levels were assessed at baseline and at the end of the administrations. Results EMPA administration reduced body weight, as well as blood glucose and cholesterol levels in animals with MS. EMPA decreased anaerobic glycolysis products (UDP-glucose, Lactic acid) and ketone bodies (β-hydroxybutyrate, acetoacetic acid) in both healthy animals and mice with MS. Additionally, an increase in ATP, accompanied by a decrease in AMP and ADP were observed in the EMPA-I/R group, compared to the DMSO-I/R group. Regarding the lipidomic analysis, gangliosides GM3 emerged as the major lipid group decreased by EMPA treatment. Lastly, despite significant changes were presented in the metabolic and lipid profile between healthy animals and those with MS, the effects of EMPA on myocardial metabolic and lipid profile were the same, regardless of the presence of MS. Conclusion(s) EMPA administration induces metabolic changes in the heart tissue and improves myocardial energetics upon myocardial I/R injury. Also, EMPA suppresses gangliosides GM3, a lipid group that has been associated with neutrophil activation and recruitment. Importantly, the effects of EMPA on myocardial metabolic and lipid profile following I/R is independent of the presence of MS.