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Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy

Kamel, S M ; van Opbergen, C J M ; Koopman, C D ; Verkerk, A O ; Boukens, B J D ; de Jonge, B ; Onderwater, Y L ; van Alebeek, E ; Chocron, S ; Polidoro Pontalti, C ; Weuring, W J ; Vos, M A ; de Boer, T P ; van Veen, T A B ; Bakkers, J

Nature communications, 2021-12, Vol.12 (1), p.7151-15, Article 7151 [Periódico revisado por pares]

England: Nature Publishing Group

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Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy
Autor: Kamel, S M ; van Opbergen, C J M ; Koopman, C D ; Verkerk, A O ; Boukens, B J D ; de Jonge, B ; Onderwater, Y L ; van Alebeek, E ; Chocron, S ; Polidoro Pontalti, C ; Weuring, W J ; Vos, M A ; de Boer, T P ; van Veen, T A B ; Bakkers, J
Assuntos: Action potential ; Age ; Alternan ; Animals ; Bioaccumulation ; Calcium ; Calcium (intracellular) ; Calcium - metabolism ; Calcium ions ; Calcium signalling ; Calcium-Binding Proteins - genetics ; Calcium-Binding Proteins - metabolism ; Cardiomyopathy ; Cardiomyopathy, Dilated - genetics ; Cardiomyopathy, Dilated - metabolism ; Cardiomyopathy, Dilated - physiopathology ; Cellular structure ; Danio rerio ; Decay rate ; Disease Models, Animal ; Echocardiography ; Embryos ; Etiocholanolone - administration & dosage ; Etiocholanolone - analogs & derivatives ; Female ; Fibrosis ; Gene Knock-In Techniques ; Hereditary diseases ; Humans ; Intracellular ; Male ; Muscle contraction ; Mutation ; Myocardial Contraction ; Myocardium - metabolism ; Phenotypes ; Phospholamban ; Sequence Deletion ; Zebrafish ; Zebrafish - genetics ; Zebrafish - metabolism
É parte de: Nature communications, 2021-12, Vol.12 (1), p.7151-15, Article 7151
Descrição: The heterozygous Phospholamban p.Arg14del mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. This mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca dynamics. Little is known about the physiological processes preceding induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we address these issues using a knock-in Phospholamban p.Arg14del zebrafish model. Hearts from adult zebrafish with this mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography reveals contractile variations before overt structural changes occur, which correlates at the cellular level with action potential duration alternans. These functional alterations are preceded by diminished Ca transient amplitudes in embryonic hearts as well as an increase in diastolic Ca level, slower Ca transient decay and longer Ca transients in cells of adult hearts. We find that istaroxime treatment ameliorates the in vivo Ca dysregulation, rescues the cellular action potential duration alternans, while it improves cardiac relaxation. Thus, we present insight into the pathophysiology of Phospholamban p.Arg14del cardiomyopathy.
Editor: England: Nature Publishing Group
Idioma: Inglês

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Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy

Kamel, S M ; van Opbergen, C J M ; Koopman, C D ; Verkerk, A O ; Boukens, B J D ; de Jonge, B ; Onderwater, Y L ; van Alebeek, E ; Chocron, S ; Polidoro Pontalti, C ; Weuring, W J ; Vos, M A ; de Boer, T P ; van Veen, T A B ; Bakkers, J

England: Nature Publishing Group

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