PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease involving ventricular remodeling.
• The molecular mechanisms underlying desmosomal mutation-induced ACM are not fully understood.

Purpose of the Study:

• To investigate the molecular pathways affected by a novel desmoplakin mutation in ACM.
• To explore the therapeutic potential of targeting PITX2 in ACM.

Main Methods:

• Identified a novel desmoplakin mutation in an ACM patient.
• Utilized CRISPR-Cas9 to correct the mutation in patient-derived human induced pluripotent stem cells (hiPSCs).
• Generated a knockin hiPSC line with the same mutation for comparative studies.

Main Results:

• Mutant cardiomyocytes showed reduced levels of connexin 43, NaV1.5, and desmosomal proteins, with prolonged action potential duration.
• The transcription factor paired-like homeodomain 2 (PITX2) was induced in mutant cardiomyocytes.
• Knockdown of PITX2 in patient-derived cardiomyocytes restored levels of desmoplakin, connexin 43, and NaV1.5.

Conclusions:

• A novel desmoplakin mutation contributes to ACM pathogenesis through PITX2 induction.
• PITX2 plays a critical role in repressing key cardiac proteins in ACM.
• Targeting PITX2 offers a potential therapeutic strategy for arrhythmogenic cardiomyopathy.