Targeting DNA damage signaling in atherosclerosis: molecular mechanisms and therapeutic opportunities

Atherosclerosis is a lipid-driven, chronic inflammatory disease of large and medium-sized arteries that underlies major cardiovascular events and remains a leading cause of mortality and morbidity worldwide. It is characterized by the progressive formation of lipid-rich plaques within the arterial wall, which can narrow the vascular lumen or trigger thrombosis after plaque rupture. During the last decade, extensive evidence has indicated that DNA damage is prevalent in vascular cells and inflammatory cells within atherosclerotic lesions. The DNA damage response (DDR) detects, signals, and repairs DNA lesions in vascular cells, transient activation preserves genomic stability and vascular homeostasis, whereas persistent or dysregulated DDR can promote atherosclerosis. Moreover, DNA damage can lead to the export of damaged DNA into the cytoplasm, triggering the activation of cytoplasmic DNA sensors and thereby aggravating inflammation in atherosclerosis. This review summarizes the current understanding of DNA damage signaling (both DDR and cytoplasmic DNA sensors) during the progression of atherosclerosis. We also review how the DDR in specific vascular cell types drives atherosclerosis. Moreover, we also discuss potential therapeutic approaches aimed at attenuating DNA damage or inhibiting DDR overactivation in atherosclerosis while highlighting that DDR-targeted therapy for atherosclerosis remains at an early exploratory stage and requires large, mechanism-oriented clinical studies.