CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
In pre-diabetic hearts, Sarcoplasmic Reticulum (SR) Ca2+ leak, mitochondria Ca2+ overload, and SR-mitochondria miscommunication culminate in apoptosis
Autor/es:
LOPEZ SOFIA; CELESTE VILLA ABRILLE ; MARILEN FEDERICO,; MAITE ZAVALA; JULIETA PALOMEQUE; ENRIQUE PORTIANSKY; ALICIA MATTIAZZI
Lugar:
Beijing
Reunión:
Congreso; 2019 XXIII ISHR WORLD CONGRESS; 2019
Resumen:
Prediabetic hearts presents Ca2+mishandling, Ca2+-calmodulin kinase II (CaMKII) hyperactivity, mitochondria dysfunction, enhanced proximity between SR-mitochondria and apoptosis. The SR-mitochondria interplay is pivotal in patho-physiological situations. Among proteins implicated in microdomains, mitofusin2 (Mfn-2), glucose-regulated protein (GRP75) and voltage-dependent anion channel (VDAC) could be involved in the miscommunication between these organelles in prediabetic hearts. We hypothesize that in prediabetic hearts, SR-Ca2+-leak is due to increased ryanodine receptors 2 (RyR2) activity via a CaMKII-dependent pathway, which in turn produces mitochondrial-Ca2+ overload and that an increased expression of Mfn-2, GRP75 and VDAC plays a role in the enhanced SR-mitochondria proximity of prediabetic hearts.We measured spontaneous Ca2+ release events (SCaRE), 3H-Ryanodine ([3H]Ry) binding assay, mitochondria Ca2+ retention capacity (CRC) and morphology, and Mfn-2, GRP75 and VDAC expression in a prediabetic model induced by fructose rich diet (FRD) in WT and AC3I mice, which express a CaMKII-inhibitor at heart level. Confocal images showed significantly increased SCaRE in WT-FRD vs. WT-CD myocytes, while in AC3I-FRD and AC3I-CD did not. [3H]Ry binding assay revealed higher Bmax (40.8±2.1ftmol/mgprotein) in WT-FRD than WT-CD (29.9±4.1) and AC3I-FRD (23.7±4.4). In isolated mitochondria, CRC decreased in WT-FRD vs. WT-CD (2.78±0.39 vs 4.26±0.73). Transmission Electron Microscopy photographs showed that mitochondria area (1.15±0.02 vs. 1.03±0.01) and diameter (1.16±0.004 vs. 1.11±0.004) were decrease in WT-FRD respect to WT-CD, whereas feret diameter (1.26±0.01 vs 1.17±0.0045) and roundness (1.36±0.004 vs. 1.26±0.001) was higher in WT-FRD than WT-CD, suggesting that mitochondria-fission might occur. A clear disarrangement in WT-FRD tissue was evident, which was not apparent in AC3I-FRD. No differences were found in Mfn-2, GRP75 or VDAC expression. We conclude that CaMKII is involved in RyR2 activity increased, SR-Ca2+ leak and mitochondria-morphology changes of FRD. Moreover, the increased in SR-Ca2+ leak and SR-mitochondria proximity would favor the decreased CRC. However, Mfn-2, GRP75 and VDAC expression were not dependent on FRD or CaMKII activity.