BackgroundMetabolic syndrome (MetS) is a prevalent risk factor for cardiac dysfunction. Although SGLT2-inhibitors have important cardioprotective effects in hyperglycemia, their underlying mechanisms are complex and not completely understood. Therefore, we examined mechanisms of a SGLT2-inhibitor dapagliflozin (DAPA)-related cardioprotection in overweight insulin-resistant MetS-rats comparison with insulin (INSU), behind its glucose-lowering effect.MethodsA 28-week high-carbohydrate diet-induced MetS-rats received DAPA (5 mg/kg), INSU (0.15 mg/kg) or vehicle for 2 weeks. To validate MetS-induction, we monitored all animals weekly by measuring body weight, blood glucose and HOMO-IR index, electrocardiograms, heart rate, systolic and diastolic pressures.ResultsDAPA-treatment of MetS-rats significantly augmented the increased blood pressure, prolonged Q–R interval, and low heart rate with depressed left ventricular function and relaxation of the aorta. Prolonged-action potentials were preserved with DAPA-treatment, more prominently than INSU-treatment, at most, through the augmentation in depressed voltage-gated K+-channel currents. DAPA, more prominently than INSU-treatment, preserved the depolarized mitochondrial membrane potential, and altered mitochondrial protein levels such as Mfn-1, Mfn-2, and Fis-1 as well as provided significant augmentation in cytosolic Ca2+-homeostasis. Furthermore, DAPA also induced significant augmentation in voltage-gated Na+-currents and intracellular pH, and the cellular levels of increased oxidative stress, protein-thiol oxidation and ADP/ATP ratio in cardiomyocytes from MetS rats. Moreover, DAPA-treatment normalized the increases in the mRNA level of SGLT2 in MetS-rat heart.ConclusionsOverall, our data provided a new insight into DAPA-associated cardioprotection in MetS rats, including suppression of prolonged ventricular-repolarization through augmentation of mitochondrial function and oxidative stress followed by improvement of fusion–fission proteins, out of its glucose-lowering effect.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0790-0) contains supplementary material, which is available to authorized users.

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The Zn in cardiomyocytes is buffered by structures near T-tubulus and/or sarcoplasmic/endoplasmic reticulum (S(E)R) while playing roles as either an antioxidant or a toxic agent, depending on the concentration. Therefore, we aimed first to examine a direct effect of ZnPO (extracellular exposure) or Zn pyrithione (ZnPT) (intracellular exposure) application on the structure of the mitochondrion in ventricular cardiomyocytes by using histological investigations. The light microscopy data demonstrated that Zn exposure induced marked increases on cellular surface area, an indication of hypertrophy, in a concentration-dependent manner. Furthermore, a whole-cell patch-clamp measurement of cell capacitance also supported the hypertrophy in the cells. We observed marked increases in mitochondrial matrix/cristae area and matrix volume together with increased lysosome numbers in ZnPO- or ZnPT-incubated cells by using transmission electron microscopy, again in a concentration-dependent manner. Furthermore, we observed notable clustering and vacuolated mitochondrion, markedly disrupted and damaged myofibrils, and electron-dense small granules in Zn-exposed cells together with some implications of fission-fusion defects in the mitochondria. Moreover, we observed marked depolarization in mitochondrial membrane potential during 1-μM ZnPT minute applications by using confocal microscopy. We also showed that 1-μM ZnPT incubation induced significant increases in the phosphorylation levels of GSK3β (Ser21 and Ser9), Akt (Ser473), and NFκB (Ser276 and Thr254) together with increased expression levels in ER stress proteins such as GRP78 and calregulin. Furthermore, a new key player at ER-mitochondria sites, promyelocytic leukemia protein (PML) level, was markedly increased in ZnPT-incubated cells. As a summary, our present data suggest that increased cytosolic free Zn can induce marked alterations in mitochondrion morphology as well as depolarization in mitochondrion membrane potential and changes in some cytosolic signaling proteins as well as a defect in ER-mitochondria cross talk.

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Role of β3‐AR dysregulation, as either cardio‐conserving or cardio‐disrupting mediator, remains unknown yet. Therefore, we examined the molecular mechanism of β3‐AR activation in depressed myocardial contractility using a specific agonist CL316243 or using β3‐AR overexpressed cardiomyocytes. Since it has been previously shown a possible correlation between increased cellular free Zn2+ ([Zn2+]i) and depressed cardiac contractility, we first demonstrated a relation between β3‐AR activation and increased [Zn2+]i, parallel to the significant depolarization in mitochondrial membrane potential in rat ventricular cardiomyocytes. Furthermore, the increased [Zn2+]i induced a significant increase in messenger RNA (mRNA) level of β3‐AR in cardiomyocytes. Either β3‐AR activation or its overexpression could increase cellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels, in line with significant changes in nitric oxide (NO)‐pathway, including increases in the ratios of pNOS3/NOS3 and pGSK‐3β/GSK‐3β, and PKG expression level in cardiomyocytes. Although β3‐AR activation induced depression in both Na+‐ and Ca2+‐currents, the prolonged action potential (AP) seems to be associated with a marked depression in K+‐currents. The β3‐AR activation caused a negative inotropic effect on the mechanical activity of the heart, through affecting the cellular Ca2+‐handling, including its effect on Ca2+‐leakage from sarcoplasmic reticulum (SR). Our cellular level data with β3‐AR agonism were supported with the data on high [Zn2+]i and β3‐AR protein‐level in metabolic syndrome (MetS)‐rat heart. Overall, our present data can emphasize the important deleterious effect of β3‐AR activation in cardiac remodeling under pathological condition, at least, through a cross‐link between β3‐AR activation, NO‐signaling, and [Zn2+]i pathways. Moreover, it is interesting to note that the recovery in ER‐stress markers with β3‐AR agonism in hyperglycemic cardiomyocytes is favored. Therefore, how long and to which level the β3‐AR agonism would be friend or become foe remains to be mystery, yet.

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