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

Autor: Díaz-Vesga MC; Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.; Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.; Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Pontificia Universidad Javeriana Cali, Cali 760031, Colombia., Flores-Vergara R; Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.; Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.; Advanced Center for Chronic Diseases, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380492, Chile., Riquelme JA; Advanced Center for Chronic Diseases, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380492, Chile.; Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380492, Chile., Llancaqueo M; Departamento Cardiovascular, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile., Sánchez G; Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.; Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile., Vergara C; Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7750000, Chile., Michea L; Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.; Division of Nephrology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile., Donoso P; Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile., Quest AFG; Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.; Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.; Laboratorio de Comunicaciones Celulares, Programa de Biología Celular y Molecular, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile., Olmedo I; Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile., Pedrozo Z; Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.; Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.; Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2022 Dec 30; Vol. 24 (1). Date of Electronic Publication: 2022 Dec 30.
DOI: 10.3390/ijms24010667
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje