HEART RHYTHM IS ALTERED BY Ca2+-CALMODULIN KINASE II (CaMKII) IN IMPAIRED GLUCOSE TOLERANCE MODEL

SOMMESE L; BLANCO P; VELEZ RUEDA O; CASTRO C; MATTIAZZI A; PALOMEQUE J

San Diego, CA

Congreso; World Congress of the ISHR; 2013

ISHR

Heart failure (HF) and the concomitant arrhythmias occur more frequently in people with type 2 diabetes (T2DM) than in the general population. T2DM is preceded by a state of impaired glucose tolerance (IGT) in which most diabetes complications are present but in a lower magnitude. On the other hand, CaMKII hyperactivity has been largely involved in cardiac injury through apoptosis, hypertrophy, Ca2+ mishandling and arrhythmias in different models of heart damage. However the nexus between IGT and CaMKII in the heart has never been explored in detail. To reach this goal we used an IGT model induced by a fructose-rich diet (control, C; and fructose, F; rats or mice), and we performed echocardiography, biochemical studies, reactive oxygen species (ROS), and Ca2+i measurements. F rats showed decreased contractility and increased hypertrophy by echocardiography associated with increased CaMKII activity (P-CaMKII 200.2±24.2%, and P-Thr17 of phospholamban 269.0±51.4%) and ROS (206.7±28.5%) with respect to C rats (100%). Isolated myocytes from F rats showed decreased inotropic reserve to isoproterenol with alternans and increased non stimulated events, NSE (C 16.24±6.00 vs F 52.27±12.95 NSE/10 min); which were prevented by pretreatment of the myocytes with KN93, a CaMKII inhibitor. Moreover, F SR-AIP mice (which express the CaMKII autocamtide inhibitory peptide [AIP] selectively at the SR membranes) show less spontaneous activity, waves and sparks than their matched F control mice. In addition, CaMKII was found singnificantly more oxidazed in F than in control rats and ryanodine receptor (RyR) was significantly more phosphorylated at the CaMKII site in F than in C rats. Furthermore F control mice co-treated with tempol, a membrane permeable scavenger, completely abolish the spontaneous activity, sparks and waves induced by the treatment with fructose alone. Altogether, the results would indicate that CaMKII activation by ROS induces cardiac dysrhythmia by a leaky phosphoylated RyR in IGT.