Protein Aggregation Is an Early Manifestation of Phospholamban p.(Arg14del)-Related Cardiomyopathy
| Autor: | Tim R Eijgenraam, Cornelis J. Boogerd, Xiaoke Yin, Manuel Mayr, Lukas E Schmidt, Herman H W Silljé, Eva van Rooij, Peter van der Meer, Nienke M Stege, Martin M Dokter, Rudolf A. de Boer, Vivian Oliveira Nunes Teixeira, Jolanda van der Velden, Konstantinos Theofilatos |
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| Přispěvatelé: | Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Hubrecht Institute for Developmental Biology and Stem Cell Research, Physiology, ACS - Heart failure & arrhythmias |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cardiomyopathy
Dilated cardiomyopathies endocrine system Heart Failure/metabolism Mutation/genetics Cardiomyopathy Dilated/genetics Cardiomyopathy Myocardium/metabolism Cardiomyopathies/genetics heart failure Mice Transgenic Protein aggregation Proteomics medicine.disease_cause Bioinformatics Transgenic Protein Aggregates Mice proteomics medicine Protein Aggregates/physiology Gene Mutation business.industry Myocardium Calcium-Binding Proteins Original Articles medicine.disease Pathophysiology Phospholamban animals Phenotype Dilated/genetics Heart failure ComputingMethodologies_DOCUMENTANDTEXTPROCESSING mutation Cardiology and Cardiovascular Medicine business |
| Zdroj: | Circulation-Heart failure, 14(11):e008532. LIPPINCOTT WILLIAMS & WILKINS Circulation. Heart failure, 14(11). Lippincott Williams and Wilkins Ltd. Circulation. Heart failure, 14(11). Lippincott Williams and Wilkins Circulation. Heart Failure Eijgenraam, T R, Boogerd, C J, Stege, N M, Oliveira Nunes Teixeira, V, Dokter, M M, Schmidt, L E, Yin, X, Theofilatos, K, Mayr, M, van der Meer, P, van Rooij, E, van der Velden, J, Silljé, H H W & de Boer, R A 2021, ' Protein Aggregation Is an Early Manifestation of Phospholamban p.(Arg14del)-Related Cardiomyopathy : Development of PLN-R14del-Related Cardiomyopathy ', Circulation. Heart failure, vol. 14, no. 11, pp. e008532 . https://doi.org/10.1161/CIRCHEARTFAILURE.121.008532 |
| ISSN: | 1941-3289 |
| DOI: | 10.1161/circheartfailure.121.008532 |
| Popis: | Supplemental Digital Content is available in the text. Background: The p.(Arg14del) pathogenic variant (R14del) of the PLN (phospholamban) gene is a prevalent cause of cardiomyopathy with heart failure. The exact underlying pathophysiology is unknown, and a suitable therapy is unavailable. We aim to identify molecular perturbations underlying this cardiomyopathy in a clinically relevant PLN-R14del mouse model. Methods: We investigated the progression of cardiomyopathy in PLN-R14Δ/Δ mice using echocardiography, ECG, and histological tissue analysis. RNA sequencing and mass spectrometry were performed on cardiac tissues at 3 (before the onset of disease), 5 (mild cardiomyopathy), and 8 (end stage) weeks of age. Data were compared with cardiac expression levels of mice that underwent myocardial ischemia-reperfusion or myocardial infarction surgery, in an effort to identify alterations that are specific to PLN-R14del–related cardiomyopathy. Results: At 3 weeks of age, PLN-R14Δ/Δ mice had normal cardiac function, but from the age of 4 weeks, we observed increased myocardial fibrosis and impaired global longitudinal strain. From 5 weeks onward, ventricular dilatation, decreased contractility, and diminished ECG voltages were observed. PLN protein aggregation was present before onset of functional deficits. Transcriptomics and proteomics revealed differential regulation of processes involved in remodeling, inflammation, and metabolic dysfunction, in part, similar to ischemic heart disease. Altered protein homeostasis pathways were identified exclusively in PLN-R14Δ/Δ mice, even before disease onset, in concert with aggregate formation. Conclusions: We mapped the development of PLN-R14del–related cardiomyopathy and identified alterations in proteostasis and PLN protein aggregation among the first manifestations of this disease, which could possibly be a novel target for therapy. |
| Databáze: | OpenAIRE |
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