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

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Systems Biology

Background:

• Atrial fibrillation (AF) is a common arrhythmia with elusive genetic causes.
• Genome-wide association studies (GWASs) have identified several AF risk loci, but their functional roles remain unclear.
• Understanding the interplay of AF-related genes and molecular mechanisms is crucial for elucidating AF pathogenesis.

Purpose of the Study:

• To investigate the functional role of Pitx2 in AF pathogenesis.
• To analyze the expression of AF GWAS-associated genes and calcium handling genes in Pitx2 loss-of-function models.
• To explore the regulatory network orchestrated by Pitx2 in atrial arrhythmogenesis.

Main Methods:

• Utilized two distinct Pitx2 loss-of-function mouse models (Sox2CrePitx2 and NppaCrePitx2).
• Performed molecular analyses of left atrial appendage tissue to assess gene expression.
• Conducted functional assessments of calcium homeostasis and microRNA expression.

Main Results:

• Pitx2 deficiency impaired expression of AF GWAS genes (Zfhx3, Kcnn3, Wnt8a) and calcium handling genes (Atp2a2, Casq2, Plb) in a dose-dependent manner.
• Calcium homeostasis was significantly altered in Pitx2-deficient mice.
• MicroRNA expression profiles were modulated by Pitx2 loss and Wnt8 overexpression.

Conclusions:

• Demonstrated a dose-dependent link between Pitx2 expression and AF susceptibility genes, calcium handling, and microRNAs.
• Identified a complex regulatory network governed by Pitx2 with significant implications for atrial arrhythmogenesis.
• Provided insights into the molecular mechanisms underlying AF development.