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Polycystin-1 Is a Crucial Regulator of BIN1 Expression and T-Tubule Remodeling Associated with the Development of Dilated Cardiomyopathy

Cardiomyopathy is commonly observed in patients with autosomal dominant polycystic kidney disease (ADPKD), even when they have normal renal function and arterial pressure. The role of cardiomyocyte polycystin-1 (PC1) in cardiovascular pathophysiology remains unknown. PC1 is a potential regulator of...

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Autores principales: Díaz-Vesga, Magda C., Flores-Vergara, Raúl, Riquelme, Jaime A., Llancaqueo, Marcelo, Sánchez, Gina, Vergara, Cecilia, Michea, Luis, Donoso, Paulina, Quest, Andrew F. G., Olmedo, Ivonne, Pedrozo, Zully
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820588/
https://www.ncbi.nlm.nih.gov/pubmed/36614108
http://dx.doi.org/10.3390/ijms24010667
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author Díaz-Vesga, Magda C.
Flores-Vergara, Raúl
Riquelme, Jaime A.
Llancaqueo, Marcelo
Sánchez, Gina
Vergara, Cecilia
Michea, Luis
Donoso, Paulina
Quest, Andrew F. G.
Olmedo, Ivonne
Pedrozo, Zully
author_facet Díaz-Vesga, Magda C.
Flores-Vergara, Raúl
Riquelme, Jaime A.
Llancaqueo, Marcelo
Sánchez, Gina
Vergara, Cecilia
Michea, Luis
Donoso, Paulina
Quest, Andrew F. G.
Olmedo, Ivonne
Pedrozo, Zully
author_sort Díaz-Vesga, Magda C.
collection PubMed
description Cardiomyopathy is commonly observed in patients with autosomal dominant polycystic kidney disease (ADPKD), even when they have normal renal function and arterial pressure. The role of cardiomyocyte polycystin-1 (PC1) in cardiovascular pathophysiology remains unknown. PC1 is a potential regulator of BIN1 that maintains T-tubule structure, and alterations in BIN1 expression induce cardiac pathologies. We used a cardiomyocyte-specific PC1-silenced (PC1-KO) mouse model to explore the relevance of cardiomyocyte PC1 in the development of heart failure (HF), considering reduced BIN1 expression induced T-tubule remodeling as a potential mechanism. PC1-KO mice exhibited an impairment of cardiac function, as measured by echocardiography, but no signs of HF until 7–9 months of age. Of the PC1-KO mice, 43% died suddenly at 7 months of age, and 100% died after 9 months with dilated cardiomyopathy. Total BIN1 mRNA, protein levels, and its localization in plasma membrane-enriched fractions decreased in PC1-KO mice. Moreover, the BIN1 + 13 isoform decreased while the BIN1 + 13 + 17 isoform was overexpressed in mice without signs of HF. However, BIN1 + 13 + 17 overexpression was not observed in mice with HF. T-tubule remodeling and BIN1 score measured in plasma samples were associated with decreased PC1-BIN1 expression and HF development. Our results show that decreased PC1 expression in cardiomyocytes induces dilated cardiomyopathy associated with diminished BIN1 expression and T-tubule remodeling. In conclusion, positive modulation of BIN1 expression by PC1 suggests a novel pathway that may be relevant to understanding the pathophysiological mechanisms leading to cardiomyopathy in ADPKD patients.
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spelling pubmed-98205882023-01-07 Polycystin-1 Is a Crucial Regulator of BIN1 Expression and T-Tubule Remodeling Associated with the Development of Dilated Cardiomyopathy Díaz-Vesga, Magda C. Flores-Vergara, Raúl Riquelme, Jaime A. Llancaqueo, Marcelo Sánchez, Gina Vergara, Cecilia Michea, Luis Donoso, Paulina Quest, Andrew F. G. Olmedo, Ivonne Pedrozo, Zully Int J Mol Sci Article Cardiomyopathy is commonly observed in patients with autosomal dominant polycystic kidney disease (ADPKD), even when they have normal renal function and arterial pressure. The role of cardiomyocyte polycystin-1 (PC1) in cardiovascular pathophysiology remains unknown. PC1 is a potential regulator of BIN1 that maintains T-tubule structure, and alterations in BIN1 expression induce cardiac pathologies. We used a cardiomyocyte-specific PC1-silenced (PC1-KO) mouse model to explore the relevance of cardiomyocyte PC1 in the development of heart failure (HF), considering reduced BIN1 expression induced T-tubule remodeling as a potential mechanism. PC1-KO mice exhibited an impairment of cardiac function, as measured by echocardiography, but no signs of HF until 7–9 months of age. Of the PC1-KO mice, 43% died suddenly at 7 months of age, and 100% died after 9 months with dilated cardiomyopathy. Total BIN1 mRNA, protein levels, and its localization in plasma membrane-enriched fractions decreased in PC1-KO mice. Moreover, the BIN1 + 13 isoform decreased while the BIN1 + 13 + 17 isoform was overexpressed in mice without signs of HF. However, BIN1 + 13 + 17 overexpression was not observed in mice with HF. T-tubule remodeling and BIN1 score measured in plasma samples were associated with decreased PC1-BIN1 expression and HF development. Our results show that decreased PC1 expression in cardiomyocytes induces dilated cardiomyopathy associated with diminished BIN1 expression and T-tubule remodeling. In conclusion, positive modulation of BIN1 expression by PC1 suggests a novel pathway that may be relevant to understanding the pathophysiological mechanisms leading to cardiomyopathy in ADPKD patients. MDPI 2022-12-30 /pmc/articles/PMC9820588/ /pubmed/36614108 http://dx.doi.org/10.3390/ijms24010667 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Díaz-Vesga, Magda C.
Flores-Vergara, Raúl
Riquelme, Jaime A.
Llancaqueo, Marcelo
Sánchez, Gina
Vergara, Cecilia
Michea, Luis
Donoso, Paulina
Quest, Andrew F. G.
Olmedo, Ivonne
Pedrozo, Zully
Polycystin-1 Is a Crucial Regulator of BIN1 Expression and T-Tubule Remodeling Associated with the Development of Dilated Cardiomyopathy
title Polycystin-1 Is a Crucial Regulator of BIN1 Expression and T-Tubule Remodeling Associated with the Development of Dilated Cardiomyopathy
title_full Polycystin-1 Is a Crucial Regulator of BIN1 Expression and T-Tubule Remodeling Associated with the Development of Dilated Cardiomyopathy
title_fullStr Polycystin-1 Is a Crucial Regulator of BIN1 Expression and T-Tubule Remodeling Associated with the Development of Dilated Cardiomyopathy
title_full_unstemmed Polycystin-1 Is a Crucial Regulator of BIN1 Expression and T-Tubule Remodeling Associated with the Development of Dilated Cardiomyopathy
title_short Polycystin-1 Is a Crucial Regulator of BIN1 Expression and T-Tubule Remodeling Associated with the Development of Dilated Cardiomyopathy
title_sort polycystin-1 is a crucial regulator of bin1 expression and t-tubule remodeling associated with the development of dilated cardiomyopathy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820588/
https://www.ncbi.nlm.nih.gov/pubmed/36614108
http://dx.doi.org/10.3390/ijms24010667
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