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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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/1/667 |
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| author | Magda C. Díaz-Vesga Raúl Flores-Vergara Jaime A. Riquelme Marcelo Llancaqueo Gina Sánchez Cecilia Vergara Luis Michea Paulina Donoso Andrew F. G. Quest Ivonne Olmedo Zully Pedrozo |
| author_facet | Magda C. Díaz-Vesga Raúl Flores-Vergara Jaime A. Riquelme Marcelo Llancaqueo Gina Sánchez Cecilia Vergara Luis Michea Paulina Donoso Andrew F. G. Quest Ivonne Olmedo Zully Pedrozo |
| author_sort | Magda C. Díaz-Vesga |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T09:58:59Z |
| format | Article |
| id | doaj.art-7cd63e0bcbc3426fb8e4ebe377f29024 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:58:59Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7cd63e0bcbc3426fb8e4ebe377f290242023-11-16T15:36:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0124166710.3390/ijms24010667Polycystin-1 Is a Crucial Regulator of BIN1 Expression and T-Tubule Remodeling Associated with the Development of Dilated CardiomyopathyMagda C. Díaz-Vesga0Raúl Flores-Vergara1Jaime A. Riquelme2Marcelo Llancaqueo3Gina Sánchez4Cecilia Vergara5Luis Michea6Paulina Donoso7Andrew F. G. Quest8Ivonne Olmedo9Zully Pedrozo10Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, ChilePrograma de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, ChileAdvanced Center for Chronic Diseases, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380492, ChileDepartamento Cardiovascular, Hospital Clínico Universidad de Chile, Santiago 8380456, ChilePrograma de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, ChileDepartamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7750000, ChilePrograma de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, ChilePrograma de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, ChileAdvanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago 8380453, ChilePrograma de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, ChilePrograma de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, ChileCardiomyopathy 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.https://www.mdpi.com/1422-0067/24/1/667BIN1polycystin-1dilated cardiomyopathyT-tubuleheart failure |
| spellingShingle | Magda C. Díaz-Vesga Raúl Flores-Vergara Jaime A. Riquelme Marcelo Llancaqueo Gina Sánchez Cecilia Vergara Luis Michea Paulina Donoso Andrew F. G. Quest Ivonne Olmedo Zully Pedrozo Polycystin-1 Is a Crucial Regulator of BIN1 Expression and T-Tubule Remodeling Associated with the Development of Dilated Cardiomyopathy International Journal of Molecular Sciences BIN1 polycystin-1 dilated cardiomyopathy T-tubule heart failure |
| 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 | BIN1 polycystin-1 dilated cardiomyopathy T-tubule heart failure |
| url | https://www.mdpi.com/1422-0067/24/1/667 |
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