Electrophysiological basis of metabolic-syndrome-induced cardiac dysfunction.
Myocardial contractility is controlled by intracellular Ca2+cycling with the contribution of sarcoplasmic reticulum (SR). In this study, we aimed to investigate the role of altered SR function in defective regulation of intracellular Ca2+levels in rats with metabolic syndrome (MetS) induced by a 16-week high-sucrose drinking-water diet. Electric-field stimulated transient intracellular Ca2+changes in MetS cardiomyocytes exhibited significantly reduced amplitude (∼30%) and prolonged time courses (2-fold), as well as depressed SR Ca2+loading (∼55%) with increased basal Ca2+level. Consistent with these data, altered ryanodine receptor (RyR2) function and SERCA2a activity were found in MetS cardiomyocytes through Ca2+spark measurements and caffeine application assay in a state in which sodium calcium exchanger was inhibited. Furthermore, tetracaine application assay results and hyperphosphorylated level of RyR2 also support the "leaky RyR2" hypothesis. Moreover, altered phosphorylation levels of phospholamban (PLN) support the depressed SERCA2a-activity thesis and these alterations in the phosphorylation of Ca2+-handling proteins are correlated with altered protein kinase and phosphatase activity in MetS cardiomyocytes. In conclusion, MetS-rat heart exhibits altered Ca2+signaling largely due to altered SR function via changes in RyR2 and SERCA2a activity. These results point to RyR2 and SERCA2a as potential pharmacological targets for restoring intracellular Ca2+homeostasis and, thereby, combatting dysfunction in MetS-rat heart.
Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey.|Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey.
Esma N
EN
Okatan
Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey.|Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey.
Aysegul Toy
AT
Durak
Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey.|Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey.
Belma
B
Turan
SERCA; calcium sparks; calcium transients; courants calciques transitoires; diabetes; diabète; fonction cardiaque; heart function; high sucrose diet; insulin resistance; régime à haute teneur en sucrose; résistance à l’insuline; étincelles calciques