Impaired glucose tolerance induces cardiac apoptosis mediated by CaMKII

SOMMESE L; BLANCO P; VELEZ RUEDA O; CASTRO C; ZANUZZI C; PORTIANSKY E; DEDMAN J; KAETZEL M; MATTIAZZI A; PALOMEQUE J

San Diego, CA

Congreso; World Congress of the ISHR; 2013

ISHR

Apoptosis is one of the more important steps leading to cardiac dysfunction and heart failure (HF), and this disease occurs more frequently in people with type 2 diabetes than in the general population. Impaired glucose tolerance (IGT), which is the mayor clinical characteristic of the prediabetic state, presents most diabetes complications, including diabetic cardiomyopathy, but in a lower magnitude. Moreover, CaMKII hyperactivity is a well recognized molecule involved in cardiac apoptosis, hypertrophy, Ca2+ mishandling and arrhythmias. However, apoptosis in IGT hearts was not clearly defined. Even less known is the connection between CaMKII and IGT. The aim of the present study was to evaluate the presence of cardiac apoptosis in an IGT model and its putative link with CaMKII activity. IGT model was induced by a fructose-rich diet (control, C; and fructose, F; rats or mice). In these animals, echocardiography, biochemical studies, reactive oxygen species (ROS), and Ca2+i measurements were performed. F rats showed decreased contractility and increased hypertrophy (echocardiography) associated with increased CaMKII and p38MAPK activity (P-CaMKII 191.6±18.3%, P-Thr17 of phospholamban 227.6±28.6%, and P-p38MAPK 161.7±13.9%) and ROS (185.4±28.6%) with respect to C rats (100%). Moreover, the apoptotic ratio Bax/Bcl2 was increased (273.6±39.7%) as well as TUNEL positive nuclei in F vs C rats. Isolated myocytes from F rats showed no difference in Ca2+ handling but significantly lower diastolic Ca2+. F SR-AIP mice (which express the CaMKII autocamtide inhibitory peptide [AIP] selectively at the SR membranes) showed less TUNEL positive nuclei than their matched F control mice. In addition, F control mice co-treated with fructose and tempol, a membrane permeable ROS scavenger, also showed less apoptosis than the one induced by the treatment with fructose alone. The results would indicate that the signaling apoptotic cascade in IGT hearts involes CaMKII-dependent phosphorylations at the SR level, ROS and p38MAPK activation.