Activating transcription factor 3 is a potential target and a new biomarker for the prognosis of atherosclerosis

ATF3 (activating transcription factor 3) is a member of the mammalian activation transcription factor/cAMP-responsive element-binding (CREB) family. It plays a role in inflammation and innate immunity, and suggests that ATF3 is associated with atherosclerosis. In our study, we analyzed datasets of atherosclerosis from the NCBI-GEO (Gene Expression Omnibus) database and found that expression levels of ATF3 were lower in macrophages from ruptured atherosclerotic plaques than from stable atherosclerotic plaques. Expression levels of ATF3 correlated with the stability of atherosclerotic plaques. KEGG analysis of different expression genes (DEGs) between ruptured and stable atherosclerotic plaques was performed by Metascape database. The PI3K-AKT pathway may be a potential pathway of the formation of ruptured atherosclerotic plaques. High-fat diet-induced atherosclerosis apoE^-/- mice were divided into two groups: a model group and an ATF3 overexpression (OE)-group. Tests on atherosclerotic plaques in the aortic root suggested that absence of ATF3 and increase of macrophages may be risk factors for the formation of ruptured atherosclerotic plaques. We found decreased areas of lesions in aortic roots and branches of aortic arch, as well as increased lesional content of macrophages as well as TUNEL-positive areas. Consistent with these results, we found reduced degradation and incidence of elastic plate cracks accompanied by suppressed MMPs expression and transduction pathway protein PI3K/AKT activation. These data suggest that ATF3 is a signaling molecule that mediates the progression and stability of atherosclerotic plaques. ATF3 could be a potential new biomarker for the prognosis of atherosclerosis and may be a therapeutic target to reduce atherosclerosis.