Cardiomyocyte cytosolic nuclear self-DNA contributes to the pathogenesis of desmoplakin cardiomyopathy

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Genetics

Background:

• Hereditary cardiomyopathies are a leading cause of heart failure and sudden cardiac death.
• Internal stressors in cardiomyopathies damage DNA, activating DNA damage response (DDR) pathways.
• Desmoplakin (DSP) cardiomyopathy is a significant hereditary condition with unclear molecular mechanisms.

Purpose of the Study:

• To investigate the role of DDR pathways in a mouse model of DSP cardiomyopathy.
• To determine if DDR activation is pathogenic in this model.
• To explore the therapeutic potential of targeting DDR components.

Main Methods:

• Utilized a genetically engineered mouse model (Myh6-MerCreMerTam Dspfl/fl) lacking the Dsp gene in cardiomyocytes.
• Assessed cardiac function, survival, histology (fibrosis, cell death), and molecular markers of DDR activation.
• Investigated the impact of deleting the cyclic GMP-AMP synthase (CGAS) gene (Mb21d1) in the disease model.

Main Results:

• DSP-deficient mice exhibited premature death, cardiac dysfunction, fibrosis, and inflammation, mirroring human DSP cardiomyopathy.
• Increased cytosolic nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) were observed in cardiomyocytes.
• Upregulation of DDR proteins (CGAS) and inflammatory pathway transcripts (IRF3, NF-κB) confirmed DDR activation.
• CGAS deletion significantly improved survival, cardiac function, and reduced pathological hallmarks.

Conclusions:

• DDR pathways are activated and contribute to pathogenesis in DSP cardiomyopathy.
• Cytosolic self-DNA accumulation triggers pathogenic DDR signaling.
• Genetic inhibition of CGAS demonstrates therapeutic efficacy, highlighting CGAS as a potential therapeutic target for DSP cardiomyopathy.