Obective: Catestatin is a cationic and hydrophobic peptide derived from the enzymatic cleavage of the prohormone Chromogranin-A. Initially identified as a potent endogenous nicotinic–cholinergic antagonist, Catestatin has recently been shown to act as a novel regulator of cardiac function and blood pressure and as a cardioprotective agent in both pre- and post-conditioning through Akt dependent mechanisms. The aim of this study was to investigate the potential role of Catestatin also on cardiac metabolism modulation, particularly on cardiomyocyte glucose uptake. Methods: Experiments were performed on isolated adult rat cardiomyocytes. Glucose uptake was assessed by fluorescent glucose incubation and confocal microscope analysis. Glut4 plasma membrane translocation was studied by immunofluorescence experiments and evaluation of peripheral/internal Glut4 staining. Furthermore, we performed immunoblot experiments to investigate the involvement of the intracellular pathway Akt/AS160 in the Catestatin dependent Glut4 trafficking. Results: Our results show that 10INS; nM Catestatin induces a significant increase in fluorescent glucose uptake, comparable to that exerted by 100 nM insulin which can be reverted by 100 nM Wortmannin (mean fluorescence intensity was 101.7INS; ±INS; 13.8 in control, 346INS; ±INS; 40.3 for Catestatin, 300.2INS; ±INS; 42.7 for Ins, 137.12INS; ±INS; 19.63 for CatestatinINS; +INS; Wm). Moreover, Catestatin stimulates Glut4 translocation to plasma membrane (peripheral/internal Glut4 staining was 0.86INS; ±INS; 0,04 in Contr, 1.23INS; ±INS; 0,08 for Cts, 1.04INS; ±INS; 0.04 for Ins, 0.84INS; ±INS; 0.02 for CtsINS; +INS; Wm) and phosphorylation of both Akt and AS160. All these effects were inhibited by Wortmannin. Conclusions: On the whole, we show for the first time that Catestatin is able to modulate cardiac glucose metabolism, by inducing an increase in glucose uptake through Glut4 translocation to the plasma membrane, and that this mechanism is mediated by the Akt/AS160 intracellular pathway. Catestatin could therefore be an alternative agonist in respect to Insulin to increase glucose uptake in the heart, potentially relevant in diabetic cardiac malfunction.
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