DOI: 10.25345/c55002
title: MassIVE MSV000088582 - The cardioprotective effect of SGLT-2 inhibitors Empagliflozin, Dapagliflozin and Ertugliflozin, in a non-diabetic mouse model of myocardial ischemia reperfusion injury: The first comparative study.
title: Background: Empagliflozin (EMPA), Dapagliflozin (DAPA) and Ertugliflozin (ERTU) are selective sodium glucose co-transporter 2 inhibitors (SGLT2i) and established drugs against type 2 diabetes mellitus (T2DM). The cardiovascular clinical trial outcomes among them differ thus, therefore we aimed to compare their cardioprotective effects in terms of infarct size (IS) reduction and reveal the mechanisms of cardioprotection in non-diabetic mice. Methods: C57BL/6 mice were randomized and orally received EMPA (10mg/kg/day), DAPA (9.0mg/kg/day), ERTU (9.7mg/kg/day) or vehicle for 7 days. IS was measured upon 30 min ischemia (I), followed by 2h reperfusion (R). In a second series of experiments the ischemic myocardium was collected (10 min R), shotgun proteomic analysis was performed and several cardioprotective pathways were investigated. In a third and fourth series of experiments significant pathways through molecular analyses and mitochondrial respiratory capacity were respectively investigated. Results: Administration of EMPA and DAPA for 7 days reduced myocardial IS. ERTU did not reduce IS. Body weight and fasting blood glucose levels were not affected by the treatments. Proteomic analysis revealed mitochondrial metabolism and NF-kB signaling as significant pathways. In the SGLT2i treated animals, only EMPA increased complex I and complex II respiration. Interestingly, NF-kB activation, the activation of RISK and STAT-3 and the downstream reduction in apoptosis were evident in EMPA and DAPA groups which coincides with the IS reduction effect. Among several upstream mediators, fibroblast growth factor 2 (FGF-2) and caveolin-3 were increased in EMPA and DAPA groups. Conclusions: Short-term EMPA and DAPA, but not ERTU administration reduces IS in non-diabetic mice through concomitant STAT-3 and RISK pathways alleviation of apoptosis. Files: 210426L000001_C1.raw 210426L000003_C2.raw 210426L000005_C3.raw 210426L000007_C4.raw 210426L000009_C5.raw correspond to control Files: 210430L000003_DAPA1.raw 210430L000005_DAPA2.raw 210430L000007_DAPA3.raw 210430L000009_DAPA4.raw 210430L000011_DAPA5.raw 210430L000013_DAPA6.raw correspond to Dapagliflozin treatment Files: 210426L000014_EMPA1.raw 210430L000001_EMPA2.raw 210426L000020_EMPA4.raw 210426L000022_EMPA5.raw 210426L000024_EMPA6.raw correspond to Empagliflozin treatment Files: 210503L000003_ERTU2.raw 210503L000005_ERTU3.raw 210503L000007_ERTU4.raw 210503L000009_ERTU5.raw 210503L000011_ERTU6.raw correspond to Ertugliflozin treatment Raw files were analyzed with Proteome Discoverer 1.4 software package (Thermo Finnigan), using the SEQUEST search engine and the UniProt mouse (Mus musculus) reviewed database. Cysteine carbamidomethylation was used as fixed and methionine oxidation as variable modifications. Two missed cleavage sites were allowed and the precursor and fragment mass tolerance were set at 10 ppm and 0.05 Da respectively. False Discovery Rate was 1%.