Self-DNA by Activating the CGAS-STING1 Pathway Contributes to the Pathogenesis of Atherosclerosis.

Abstract

Purpose of review: To discuss the role of self-DNA in activating the cytosolic DNA-sensing proteins (CDSPs) and inducing low-grade inflammation in the vessel wall in coronary atherosclerosis.

Recent findings: The cytosolic self-DNA, released from the nuclear or mitochondrial DNA in response to internal and external stressors, is sensed by the cytosolic CDSPs, which activate a cascade of molecular events that lead to the expression of interferon-stimulated genes and pro-inflammatory cytokines. The focus of this review is on the cGMP-cAMP synthase (CGAS) - stimulator of interferon response cGAMP interactor 1 (STING1) pathway. Activation of the CGAS-STING1 pathway has been documented in the coronary arteries in human patients with atherosclerosis. Likewise, experimental data implicate the activation of the CGAS-STING1 pathway in response to cytosolic self-DNA in the pathogenesis of atherosclerosis and cardiac remodeling, as well as clinical outcomes after myocardial infarction. Genetic and pharmacological inhibition of the CGAS-STING1 pathway, by and large, has shown salubrious effects in attenuating atherosclerosis and improving cardiac function and prolonging survival after myocardial infarction in experimental models. The data support the pathogenic role of the cytosolic self-DNA, released from the nuclear and/or mitochondrial genomes in response to the DNA-damaging agents, in inducing a low-grade inflammation in the vessel wall and contributing to the pathogenesis of coronary atherosclerosis and cardiac remodeling post-myocardial infarction. Whether the salubrious effects of targeting the CGAS-STING1 pathway, observed in the experimental models, would extend to human patients with coronary atherosclerosis or myocardial infarction is an open empirical question that awaits being tested after careful consideration of the potential fortuitous effects.