Empagliflozin alleviates diabetic cardiomyopathy via inhibiting excessive autophagy and adverse remodeling in type 1 diabetic mice

Abstract Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular mortality in patients with and without diabetes mellitus, but underlying mechanisms remain unclear. Autophagy is an important cardioprotective mechanism under acute stress conditions, excessive autophagy can accelerate myocardial cell death leading to autosis. In this study we evaluated the role of empagliflozin (EMPA) against cardiac injury streptozotocin (STZ)-induced diabetic mice, assessed mechanisms. EMPA (10 mg/kg/die)-treated male mice had a lower number TUNEL-positive apoptotic cells (%TdT+ 4.9±2, p<0.05), percentage SA-β-gal positive senescent area (%SA-β-gal 7.9±1, fibrotic (%picrosirius red 0.15±0.06, (%green fluorescence 2.3±0.6, p<0.01), compared 4.9±2; %SA-β-gal 10±2; %picrosirius 0.24±0.08; %green autophagic 3.98±0.5). Proteomics analysis tissue showed downregulation apoptosis, necrosis 5' adenosine monophosphate-activated protein kinase (AMPK) pathways, along upstream activation vascular endothelial growth factor sirtuins heart EMPA+STZ treated STZ mice. Since leads modulation cardiomyogenic transcription factors, analyzed total expression serum response (SRF), myocardin myocardin-related (MRTF), DNA binding activity SRF by electromobility shift assay. While only increased MRTF, (2.2±0.01, p<0.01) (2.0±0.1, significantly SRF/SRE alone (0.5±0.01), which was paralleled increase actin (4.06±0.1 vs 2.2±0.01, p<0.01). reversed STZ-induced systolic dysfunction at echocardiography, pS368-connexin 43 active isoform (Table). parallel vitro experiments, inhibited high glucose-treated cardiomyocytes inhibiting inducer GSK3β, reactivation transcriptional complex for cardiomyocyte contractile genes. Our results indicate that plays effect through mTOR/AMPK axis mouse model type 1 diabetes. also promotes reverse remodeling fibrosis, activates Cx43 promyogenic program sirtuins-SRF (Figure 1), context Funding Acknowledgement Type funding sources: None.