Cytosolic DNA sensing protein pathway is activated in human hearts with dilated cardiomyopathy

Abstract

The genome is constantly exposed to numerous stressors that induce DNA lesions, including double-stranded DNA breaks (DSBs). DSBs are the most dangerous, as they induce genomic instability. In response to DNA damage, the cell activates nuclear DNA damage response (DDR) and the cytosolic DNA sensing protein (CDSP) pathways, the latter upon release of the DSBs to the cytosol. The CDSP pathway activates nuclear factor kappa B(NFκB) and interferon regulatory factor 3 (IRF3) and induces expression of the pro-inflammatory genes. There is scant data on activation of the CDSP pathway in human hearts with dilated cardiomyopathy (DCM). Thus, we determined expression levels of several components of the CDSP pathway and detected increased levels of cyclic GMP-AMP synthase (CGAS), the canonical CDSP, the TANK-binding kinase 1 (TBK1), an intermediary kinase in the pathway, and RELB, P52, and P50 components of the NFκB pathway in the cardiac samples from patients with DCM. The findings provide the first set of evidence for the activation of the CDSP pathways in human hearts with DCM.