CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
CARDIAC APOPTOSIS IN THE PREDIABETIC HEART: CaMKII , Ca MISHANDLING AND MITOCHONDRIA DYSFUNCTION
SOMMESE L ; DEDMAN J; MATTIAZZI A; ZANUZZI C; KAETZEL M; PALOMEQUE J; FEDERICO M; PORTIANSKY E; WHERENS X
Congreso; ISHR XXIII World Congress; 2016
The mitochondria is a well-known intermediate of apoptosis, which is one of the more important steps leading to heart failure (HF). This disease occurs more frequently in people with type 2 diabetes than in the general population. However, cardiac apoptosis has not been previously evaluated at the prediabetic state. Since CaMKII is involved in cardiac apoptosis and Ca2+ mishandling, the aim of the present study was to evaluate the presence of cardiac apoptosis in a prediabetic model (PM) induced by a fructose-rich diet (FRD) in rats or mice and the putative link with CaMKII activity and mitochondria dysfunction. FRD rats showed decreased contractility (echocardiography) and increased CaMKII (P-CaMKII 191.6±18.3%), and ROS (185.4±28.6%) with respect to control diet (CD) rats (100%). Moreover, the apoptotic ratio Bax/Bcl2 increased in FRD vs CD rats (273.6±39.7%) as well as TUNEL positive nuclei. Mitochondria from FRD rats showed significant more swelling (DO 0.34±0.05 CD vs 0.53±0.03 FRD), enhanced mitochondria membrane depolarization and mitochondria Ca2+ content than CD rats. Moreover, myocytes from FRD rats significantly increased sarcoplasmic reticulum (SR) Ca2+ leak vs CD myocytes. In Wild Type (WT) mice, collagen type III increased in FRD (27.06±5.24%) with respect to CD (13.33±1.23%) hearts. FRD SR-AIP mice (which express the CaMKII autocamtide inhibitory peptide [AIP] at the SR membranes) showed less TUNEL positive nuclei and no change in collagen type III than FRD WT mice. Co-treatment with tempol, a membrane permeable ROS scavenger, decreased apoptosis, collagen type III as well as SR Ca2+ leak in FRD WT mice. Moreover, mitochondria swelling could be also prevented in S2814A mice, which ryanodine receptor (RyR2) cannot be phosphorylated by CaMKII. The results would indicate a causal link between CaMKII activation by increased ROS, SR Ca2+ leak produced by CaMKII-dependent phosphorylation of RyR2 and mitochondria damage induced by Ca2+ overload.