Signaling pathway of cardiac apoptosis in impaired glucose tolerance

SOMMESE L; ZANUZZI C; PORTIANSKY E; DEDMAN J; KAETZEL M; MATTIAZZI A; PALOMEQUE J

New London

Conferencia; Gordon Research Seminars & Conference; 2014

Cardiac dysfunction observed in heart failure (HF) is due, at least in part, to apoptosis. HF occurs more frequently in people with type 2 diabetes than in the general population, and this metabolic disease is preceded by an impaired glucose tolerance (IGT) state, which is a characteristic of prediabetes. The magnitude of diabetes complications at the prediabetes stage is poorly defined and the possibility of increased apoptosis in IGT hearts has not been previously studied. On the other hand, CaMKII hyperactivity is a well recognized molecule involved in apoptosis and other cardiac derangements. The hypothesis of the present study is that the IGT model has an increased CaMKII activity which is linked to cardiac apoptosis through a mitochondrial pathway. IGT model was induced by a fructose-rich diet (control diet, CD; and fructose-rich diet, FRD; rats or mice). In these animals, echocardiography, biochemical studies, reactive oxygen species (ROS), and mitochondrial swelling experiments were performed. FRD rats showed decreased contractility and increased hypertrophy (echocardiography) associated with increased CaMKII activity (P-CaMKII 91.6±18.3%, Ox-CaMKII 27.75±7.67%, P-Thr17 of phospholamban 127.6±28.6% and P-Ser2414 of RyR2 42.23±11.25%), p38MAPK activity (P-p38MAPK 61.7±13.9%) and ROS (85.4±28.6%) with respect to CD rats. Moreover, the apoptotic ratio Bax/Bcl2 was increased by 173.6±39.7% as well as TUNEL positive nuclei in FRD vs CD rats. Isolated mitochondria from FRD rats showed significant more swelling than CD mitochondria (DO 0.34±0.05 CD vs 0.56±0.03 FRD). FRD SR-AIP mice (which express the CaMKII autocamtide inhibitory peptide [AIP] selectively at the SR membranes), showed less TUNEL positive nuclei than their matched FRD control mice. In addition, FRD 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 indicate that: 1. IGT hearts present an increase in cardiac cell death by apoptosis. 2. The apoptotic signaling pathways involves CaMKII activation, CaMKII-dependent phosphorylation of sarcoplasmic reticulum proteins, increment in ROS, p38MAPK activation and mitochondrial damage.