Genetic Ablation of the DNA Damage Response Pathway Attenuates Lamin-Associated Dilated Cardiomyopathy in Mice

Hereditary dilated cardiomyopathy (DCM) is a primary disease of cardiac myocytes caused by mutations in genes encoding proteins with a diverse array of functions. Mutations in the LMNA gene, encoding the nuclear envelope protein lamin A/C, are the second most common causes of DCM. The phenotype is characterized by progressive cardiac dysfunction, leading to refractory heart failure, myocardial fibrosis, cardiac arrhythmias, and sudden cardiac death. The molecular pathogenesis of DCM caused by the LMNA mutations is not well known. The LMNA protein is involved in nuclear membrane stability. It is also a guardian of the genome involved in the processing of the topoisomerases at the transcriptionally active domain and the repair of double-stranded DNA breaks (DSBs). Deletion of the mouse Lmna gene in cardiac myocytes leads to premature death, DCM, myocardial fibrosis, and apoptosis. The phenotype is associated with increased expression of the cytosolic DNA sensor cyclic GMP-AMP synthase (CGAS) and activation of the DNA damage response (DDR) pathway. Genetic blockade of the DDR pathway, upon knockout of the Mb21d1 gene encoding CGAS, prolonged survival, improved cardiac function, partially restored levels of molecular markers of heart failure, and attenuated myocardial apoptosis and fibrosis in the LMNA-deficient mice. The findings indicate that targeting the CGAS/DDR pathway might be beneficial in the treatment of DCM caused by mutations in the LMNA gene.