期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27461-8
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资金
- Netherlands Cardio Vascular Research Initiative (CVON): the Dutch Heart Foundation
- Dutch Federation of University Medical Centre
- Netherlands Organization for Health Research and Development
- Royal Netherlands Academy of Sciences [CVON-PREDICT 2012-10, 2018-30]
- PLN Foundation
- ZonMW [40-00812-98-12086]
- ERA-NET Cofund action under the European Union's Horizon 2020 research and innovation program [643578]
- Canadian Institutes for Health Research (CIHR)
- Netherlands Organization for Health Research and Development (ZonMw)
- Belgium (Flanders) Research Foundation Flanders (FWO)
- French National Research Agency (ANR)
- E-Rare-CoHeart project
Mutation in Phospholamban (PLN) can lead to arrhythmogenic cardiomyopathy in patients. Using a zebrafish model with the PLN p.Arg14del mutation, researchers found that istaroxime can rescue some phenotypes associated with the disease, including cardiac dysfunction and altered calcium dynamics.
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 Ca2+ 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 Ca2+ transient amplitudes in embryonic hearts as well as an increase in diastolic Ca2+ level, slower Ca2+ transient decay and longer Ca2+ transients in cells of adult hearts. We find that istaroxime treatment ameliorates the in vivo Ca2+ 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. Arrhythmogenic cardiomyopathy is a genetically inherited disease caused by deletion of an arginine in Phospholamban (PLN), a small protein that regulates intracellular calcium levels. Here the authors show that zebrafish with the PLN p.Arg14del mutation develop severe cardiomyopathy which is preceded by contractile dysfunction and altered calcium dynamics and istaroxime is identified as a small molecule that can rescues some of these phenotypes.
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