Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance

The impact of cardiac apoptosis in pre-diabetic stages of diabetic cardiomyopathy is unknown. We show that myocytes from fructose-rich diet (FRD) animals exhibit arrhythmias produced by exacerbated Ca2+/calmodulin-protein kinase (CaMKII) activity, ryanodine receptor 2 (RyR2) phosphorylation and sarc...

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Autores principales: Federico, Marilén, Portiansky, Enrique Leo, Sommese, Leandro Matías, Alvarado, Francisco J., Blanco, Paula Graciela, Zanuzzi, Carolina Natalia, Dedman, John, Kaetzel, Marcia, Wehrens, Xander H. T, Mattiazzi, Alicia, Palomeque, Julieta
Formato: Articulo
Lenguaje:Inglés
Publicado: 2017
Materias:
Ciencias Médicas
cardiac apoptosis
diabetic cardiomyopathy
fructose-rich diet
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/80286
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-80286
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Médicas
cardiac apoptosis
diabetic cardiomyopathy
fructose-rich diet
spellingShingle Ciencias Médicas
cardiac apoptosis
diabetic cardiomyopathy
fructose-rich diet
Federico, Marilén
Portiansky, Enrique Leo
Sommese, Leandro Matías
Alvarado, Francisco J.
Blanco, Paula Graciela
Zanuzzi, Carolina Natalia
Dedman, John
Kaetzel, Marcia
Wehrens, Xander H. T
Mattiazzi, Alicia
Palomeque, Julieta
Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
topic_facet Ciencias Médicas
cardiac apoptosis
diabetic cardiomyopathy
fructose-rich diet
description The impact of cardiac apoptosis in pre-diabetic stages of diabetic cardiomyopathy is unknown. We show that myocytes from fructose-rich diet (FRD) animals exhibit arrhythmias produced by exacerbated Ca2+/calmodulin-protein kinase (CaMKII) activity, ryanodine receptor 2 (RyR2) phosphorylation and sarcoplasmic reticulum (SR) Ca2+ leak. We tested the hypothesis that this mechanism also underlies cardiac apoptosis in pre-diabetes.We generated a pre-diabetic model in FRD mice. FRD mice showed an increase in oxidative stress, hypertrophy and systolic dysfunction. FRD myocytes exhibited enhanced SR Ca2+ spontaneous events in the absence of SR Ca2+ load alterations vs. control-diet (CD) myocytes. In HEK293 cells, hyperglycaemia significantly enhanced [3H]ryanodine binding and CaMKII phosphorylation of RyR2-S2814 residue vs. normoglycaemia. CaMKII inhibition prevented hyperglycaemia-induced alterations. FRD also evoked cardiac apoptosis inWT mice vs. CD-WT mice. Co-treatment with the reactive oxygen species scavenger Tempol prevented FRD-induced apoptosis inWT mice. In contrast, FRD enhanced oxidative stress but not apoptosis in FRD-SR-AIP mice, in which a CaMKII inhibitor is targeted to the SR. FRD produced mitochondrial membrane depolarization inWT mice but not in S2814A mice, in which the CaMKII phosphorylation site on RyR2 was ablated. Furthermore, FRD decreased mitochondrial area, mean Feret diameter and mean SR–mitochondrial distance vs. CD-WT hearts. This remodelling was prevented in AC3I mice, with cardiac-targeted CaMKII inhibition. CaMKII phosphorylation of RyR2, SR Ca2+ leak and mitochondrial membrane depolarization are critically involved in the apoptotic pathway of the pre-diabetic heart. The FRD-induced decrease in SR–mitochondrial distance is likely to additionally favour Ca2+ transit between the two organelles.
format Articulo
Articulo
author Federico, Marilén
Portiansky, Enrique Leo
Sommese, Leandro Matías
Alvarado, Francisco J.
Blanco, Paula Graciela
Zanuzzi, Carolina Natalia
Dedman, John
Kaetzel, Marcia
Wehrens, Xander H. T
Mattiazzi, Alicia
Palomeque, Julieta
author_facet Federico, Marilén
Portiansky, Enrique Leo
Sommese, Leandro Matías
Alvarado, Francisco J.
Blanco, Paula Graciela
Zanuzzi, Carolina Natalia
Dedman, John
Kaetzel, Marcia
Wehrens, Xander H. T
Mattiazzi, Alicia
Palomeque, Julieta
author_sort Federico, Marilén
title Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
title_short Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
title_full Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
title_fullStr Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
title_full_unstemmed Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
title_sort calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
publishDate 2017
url http://sedici.unlp.edu.ar/handle/10915/80286
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