CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
CaMKII determines arrhytmogenic events induced by acute exposure to high glucose
Autor/es:
LÓPEZ, SOFÍA; SAID, MATILDE; FEDERICO, MARILÉN; MATTIAZZI, ALICIA; NUOZZI, GUILLERMINA; PALOMEQUE, JULIETA
Lugar:
Rosario, Santa Fe
Reunión:
Congreso; SAFIS encuentro anual 2019; 2019
Resumen:
Glycaemia is continuously fine-tuned according to our food intake and consumption. However this regulation could be disrupted under certain metabolic conditions as impaired glucose tolerance, metabolic syndrome and diabetes mellitus; or even in stress context, i.e. surgery, cardiac infarct. Given that pre-diabetic and diabetic hearts present calcium (Ca2+) mishandling due, in part, by Ca2+-Calmodulin Kinase II (CaMKII) hyperactivation, we hypothesized that an acute increase in glycaemia causes Ca2+ handling abnormalities capable to trigger arrhythmias in a CaMKII dependent pathway. We used isolated mice cardiomyocytes loaded with Fura 2-AM to evaluate intracellular Ca2+ handling by epifluorescence, Langendorff perfused hearts to measure developed pressure (DP) and monophasic action potential (MAP) and hearts homogenates to perform [3H]Ryanodine binding assay to evaluate ryanodine receptor 2 (RyR2) activity.The change from normal glucose (NG) buffer (11 mM, 325.61mOsm) to high glucose (HG) buffer (25 mM, 339.26 mOsm) significantly increased Ca2+ transient (CaiT) amplitude (60.4±20.5%) and arrhythmogenic events (71.429%). A similar increment in osmolality induced by sucrose or choline chloride did not produced any effect either in CaiT or rhythmicity. The effects of HG were prevented by treatment with AIP (2.5µM), a specific CaMKII inhibitor and in S2814A mice myocytes (which have the S2814 residue of RyR2 mutated to A, unphosphorytable by CaMKII). In Langendorff perfused hearts, HG perfusion increased DP (30.0±3%) and produced ectopic beats with respect to NG perfusion. [3H]Ry binding assays showed a significantly increase in RyR2 sensitivity (1.05±0.27 vs 2.30±0.38µM) and maximal activity (Bmax: 48.09±2.35, vs 31.58±1.98) under HG vs. NG conditions.We conclude that acute administration of HG induces changes in Ca2+ handling and arrhythmic events that are dependent on CaMKII activation, probably through phosphorylation of RyR2.