A SGLT2 inhibitor dapagliflozin comparison with insulin exerts important effects on Zn2+-transporters in cardiomyocytes from insulin-resistant metabolic syndrome rats through inhibition of oxidative stress

Sodium-glucose cotransporter 2 (SGLT2)-inhibitors showed signiďŹ cant effect in patients with diabetes or metabolic syndrome, MetS with high cardiovascular-risk. Although the increased intracellular Zn2+ level ([Zn2+]i), oxidative stress and alterated cardiac matrix metalloproteinases (MMPs) in diabetic cardiomyopathy can intersect with different signaling pathways, the exact mechanisms are not known yet. Since either MMPs or SGLT2 have important role in cardiac-fibrosis under hyperglycemia, we aimed to examine the role of SGLT2-inhibitor dapagliflozin (DAP) on cardiac Zn2+-transporters responsible from [Zn2+]i-regulation, comparison to insulin (INS), together with MMP levels and systemic oxidative-stress-status in MetS-rats. High-carbohydrated diet-induced MetS-rats received DAP or INS for two weeks. DAP but not INS in MetS-rats significantly decreased high blood-glucose level, while both treatments exerted benefits on increased total-oxidative-status and decreased total-antioxidant-status in MetS-rat plasma as well as in heart tissue. Protein levels of Zn2+-transporters, responsible from Zn2+-influx into cytosol, ZIP7 and ZIP14 were decreased with no change in ZIP8 of MetS-rat cardiomyoctes, while Zn2+-transporters, responsible from cytosolic Zn2+-efflux, ZnT7 was decreased. Both treatments induced significant beneficial effects on altered ZIP14, ZIP8 and ZnT7 levels. Furthermore, both treatments exerted also benefits on depressed gelatin-zymography and protein expression levels of MMP-2 and MMP-9 in MetS-rat ventricular cardiomyocytes. The direct effect of DAP on heart was also confirmed with measurement of left ventricular developed pressure. Overall, we showed that DAP has important antioxidant-like cardio-protective effect in MetS-rats, similar to INS-effect, affecting Zn2+-regulation via Zn2+-transporters, MMPs and oxidative-stress. Therefore one can suggest that SGLT2-inhibitors can be new therapeutic agents for cardio-protection not only in hyperglycemia but also in failing heartThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author