title: Pitx2 impairs calcium handling in a dose-dependent manner by modulating Wnt signalling.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, Jaén, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Lozano-Velasco
authors.affiliation: Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, Jaén, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Hernández-Torres
authors.affiliation: Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, Jaén, Spain.
authors.forename: Houria
authors.initials: H
authors.lastname: Daimi
authors.affiliation: Cardiac Rhythm and Contraction Group, Cardiovascular Research Centre CSIC-ICCC and IIB Sant Pau, Barcelona, Spain.
authors.forename: Selma A
authors.initials: SA
authors.lastname: Serra
authors.affiliation: Cardiac Rhythm and Contraction Group, Cardiovascular Research Centre CSIC-ICCC and IIB Sant Pau, Barcelona, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Herraiz
authors.affiliation: Cardiac Rhythm and Contraction Group, Cardiovascular Research Centre CSIC-ICCC and IIB Sant Pau, Barcelona, Spain.
authors.forename: Leif
authors.initials: L
authors.lastname: Hove-Madsen
authors.affiliation: Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, Jaén, Spain.
authors.forename: Amelia
authors.initials: A
authors.lastname: Aránega
authors.affiliation: Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, Jaén, Spain dfranco@ujaen.es.
authors.forename: Diego
authors.initials: D
authors.lastname: Franco
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000032:analysis; D055748:SOXB1 Transcription Factors / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000097577:Homeobox Protein PITX2
chemical_list: D002118:Calcium; D018398:Homeodomain Proteins; D035683:MicroRNAs; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C527783:Sox2 protein, mouse; C489511:Zfhx3 protein, mouse
keywords: Atrial arrhythmias; Calcium handling; Pitx2; Wnt signalling