Back to Search
Start Over
Pitx2 impairs calcium handling in a dose-dependent manner by modulating Wnt signalling
- Source :
- CARDIOVASCULAR RESEARCH, r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau, instname
- Publication Year :
- 2015
- Publisher :
- Oxford University Press (OUP), 2015.
-
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 AFGWAS-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. ConclusionOur 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.
- Subjects :
- 0301 basic medicine
Calcium metabolism
PITX2
Atrial arrhythmias
Physiology
chemistry.chemical_element
Pitx2
Calcium
Biology
Bioinformatics
Cell biology
03 medical and health sciences
Basal (phylogenetics)
030104 developmental biology
chemistry
Physiology (medical)
microRNA
Gene expression
Calcium handling
Cardiology and Cardiovascular Medicine
Gene
Wnt signalling
Genetic association
Subjects
Details
- ISSN :
- 17553245 and 00086363
- Volume :
- 109
- Database :
- OpenAIRE
- Journal :
- Cardiovascular Research
- Accession number :
- edsair.doi.dedup.....35bb3c5e9ce0382caa6dc7b8925b62a6