Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy
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Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. / Paavola, Jere; Schliffke, Simon; Rossetti, Sandro; Kuo, Ivana Y-T; Yuan, Shiaulou; Sun, Zhaoxia; Harris, Peter C; Torres, Vicente E; Ehrlich, Barbara E.
In: J MOL CELL CARDIOL, Vol. 58, 01.05.2013, p. 199-208.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy
AU - Paavola, Jere
AU - Schliffke, Simon
AU - Rossetti, Sandro
AU - Kuo, Ivana Y-T
AU - Yuan, Shiaulou
AU - Sun, Zhaoxia
AU - Harris, Peter C
AU - Torres, Vicente E
AU - Ehrlich, Barbara E
N1 - Copyright © 2013 Elsevier Ltd. All rights reserved.
PY - 2013/5/1
Y1 - 2013/5/1
N2 - Mutations in PKD1 and PKD2, the genes encoding the proteins polycystin-1 (PC1) and polycystin-2 (PC2), cause autosomal dominant polycystic kidney disease (ADPKD). Although the leading cause of mortality in ADPKD is cardiovascular disease, the relationship between these conditions remains poorly understood. PC2 is an intracellular calcium channel expressed in renal epithelial cells and in cardiomyocytes, and is thus hypothesized to modulate intracellular calcium signaling and affect cardiac function. Our first aim was to study cardiac function in a zebrafish model lacking PC2 (pkd2 mutants). Next, we aimed to explore the relevance of this zebrafish model to human ADPKD by examining the Mayo Clinic's ADPKD database for an association between ADPKD and idiopathic dilated cardiomyopathy (IDCM). Pkd2 mutant zebrafish showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling and calcium alternans. These results indicate heart failure in the pkd2 mutants. In human ADPKD patients, we found IDCM to coexist frequently with ADPKD. This association was strongest in patients with PKD2 mutations. Our results demonstrate that PC2 modulates intracellular calcium cycling, contributing to the development of heart failure. In human subjects we found an association between ADPKD and IDCM and suggest that PKD mutations contribute to the development of heart failure.
AB - Mutations in PKD1 and PKD2, the genes encoding the proteins polycystin-1 (PC1) and polycystin-2 (PC2), cause autosomal dominant polycystic kidney disease (ADPKD). Although the leading cause of mortality in ADPKD is cardiovascular disease, the relationship between these conditions remains poorly understood. PC2 is an intracellular calcium channel expressed in renal epithelial cells and in cardiomyocytes, and is thus hypothesized to modulate intracellular calcium signaling and affect cardiac function. Our first aim was to study cardiac function in a zebrafish model lacking PC2 (pkd2 mutants). Next, we aimed to explore the relevance of this zebrafish model to human ADPKD by examining the Mayo Clinic's ADPKD database for an association between ADPKD and idiopathic dilated cardiomyopathy (IDCM). Pkd2 mutant zebrafish showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling and calcium alternans. These results indicate heart failure in the pkd2 mutants. In human ADPKD patients, we found IDCM to coexist frequently with ADPKD. This association was strongest in patients with PKD2 mutations. Our results demonstrate that PC2 modulates intracellular calcium cycling, contributing to the development of heart failure. In human subjects we found an association between ADPKD and IDCM and suggest that PKD mutations contribute to the development of heart failure.
KW - Animals
KW - Calcium
KW - Calcium Signaling
KW - Cardiomyopathy, Dilated
KW - Carrier Proteins
KW - Genetic Predisposition to Disease
KW - Humans
KW - Myocytes, Cardiac
KW - Podocytes
KW - Polycystic Kidney, Autosomal Dominant
KW - TRPP Cation Channels
KW - Zebrafish
KW - Zebrafish Proteins
U2 - 10.1016/j.yjmcc.2013.01.015
DO - 10.1016/j.yjmcc.2013.01.015
M3 - SCORING: Journal article
C2 - 23376035
VL - 58
SP - 199
EP - 208
JO - J MOL CELL CARDIOL
JF - J MOL CELL CARDIOL
SN - 0022-2828
ER -