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Pitx2 impairs calcium handling in a dose-dependent manner by modulating Wnt signalling.

2016, Cardiovasc Res. 2016 Jan 1;109(1):55-66. doi: 10.1093/cvr/cvv207. Epub 2015 Aug 4.
Lozano-Velasco E1, Hernández-Torres F1, Daimi H1, Serra SA2, Herraiz A2, Hove-Madsen L2, Aránega A1, Franco D3.
Related authors of the center Hove-Madsen Leif, Herraiz Adela .
1Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, Jaén, Spain.
2Cardiac Rhythm and Contraction Group, Cardiovascular Research Centre CSIC-ICCC and IIB Sant Pau, Barcelona, Spain.
3Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, Jaén, Spain dfranco@ujaen.es.
Abstract
AIMS:
Atrial fibrillation (AF) is the most common type of arrhythmia in humans, yet the genetic cause of AF remains elusive. Genome-wide association studies (GWASs) have reported risk variants in four distinct genetic loci, and more recently, a meta-GWAS has further implicated six new loci in AF. However, the functional role of these AF GWAS-related genes in AF and their inter-relationship remain elusive.
METHODS AND RESULTS:
To get further insights into the molecular mechanisms driven by Pitx2, calcium handling and novel AF GWAS-associated gene expression were analysed in two distinct Pitx2 loss-of-function models with distinct basal electrophysiological defects; a novel Pitx2 conditional mouse line, Sox2CrePitx2, and our previously reported atrial-specific NppaCrePitx2 line. Molecular analyses of the left atrial appendage in NppaCrePitx2(+/-) and NppaCrePitx2(-/-) adult mice demonstrate that AF GWAS-associated genes such as Zfhx3, Kcnn3, and Wnt8a are severely impaired but not Cav1, Synpo2l, nor Prrx1. In addition, multiple calcium-handling genes such as Atp2a2, Casq2, and Plb are severely altered in atrial-specific NppaCrePitx2 mice in a dose-dependent manner. Functional assessment of calcium homeostasis further underscores these findings. In addition, multiple AF-related microRNAs are also impaired. In vitro over-expression of Wnt8, but not Zfhx3, impairs calcium handling and modulates microRNA expression signature identified in Pitx2 loss-of-function models.
CONCLUSION:
Our data demonstrate a dose-dependent relation between Pitx2 expression and the expression of AF susceptibility genes, calcium handling, and microRNAs and identify a complex regulatory network orchestrated by Pitx2 with large impact on atrial arrhythmogenesis susceptibility.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
KEYWORDS:
Atrial arrhythmias; Calcium handling; Pitx2; Wnt signalling
PMID: 26243430 [PubMed - in process]

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