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

Hereditary cardiomyopathies are the prototypic forms of heart failure and major causes of sudden cardiac death. The genome in cardiomyopathies is exposed to internal stressors, which damage the DNA and activate the DNA damage response (DDR) pathways. We set out to determine whether the DDR pathways were activated and pathogenic in an established mouse model of desmoplakin (DSP) cardiomyopathy generated upon deletion of the Dsp gene in cardiomyocytes (Myh6-MerCreMerTam Dspfl/fl; Myh6-McmTam Dspfl/fl). The mice exhibited premature death, cardiac dysfunction, myocardial cell death, fibrosis, and increased expression levels of the pro-inflammatory cytokines, consistent with the phenotype of human DSP cardiomyopathy. Cytosolic nuclear self-DNA (nDNA) and mitochondrial DNA (mtDNA) were increased in cardiomyocyte cytosol in the Myh6-McmTam Dspfl/fl mice. Likewise, the DDR pathway proteins, including the cyclic GMP-AMP synthase (CGAS)/stimulator of interferon response 1, were upregulated, as were the transcript levels of interferon response factor 3 and the NF-κB target genes. Deletion of the Mb21d1 gene encoding CGAS in the Myh6-McmTam Dspfl/fl mice prolonged survival, improved cardiac function, attenuated fibrosis, and reduced cell death. Thus, cytosolic nDNA and mtDNA are increased and the DDR pathways are activated and pathogenic in a mouse model of DSP cardiomyopathy, whereas genetic blockade of CGAS is salubrious.