Abstract 15420: Cgas-Sting Pathway-Mediated Cholesterol Metabolism Promotes Atherosclerosis Formation

Abstract

Introduction: The mechanisms underlying macrophage lipid accumulation and foam cell formation, the critical step in atherosclerosis initiation, remain to be understood. The cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway triggers potent inflammation in response to cytosolic DNA accumulation. Hypothesis: In this study, we found that the cGAS-STING signaling pathway can promote macrophage lipid accumulation and atherosclerosis development. Methods: We developed an atherosclerosis mice model by a single intraperitoneal injection of an adeno-associated virus (AAV) containing a mouse PCSK9 gain-of-function mutation D377Y. Results: In the descending aorta of patients and aortic root of atherosclerotic mice, we detected profound cytosolic DNA accumulation that was associated with the activation of cGAS -STING in both human and mouse atherosclerotic plaques. In cultured macrophages, DNA uptake by macrophages activated the cGAS-STING pathway, which induced the biosynthesis of fatty acids and cholesterol. Interestingly, we found that STING can bind to SREBP2 (sterol regulatory element-binding protein 2) through SCAP (SREBP2 cleavage activating protein) and promote its cleavage and nuclear translocation, and subsequent induction of genes in fatty acid and cholesterol biosynthesis. Finally, in an AAV-PCSK9/high-fat diet-induced atherosclerosis model, cGas -/- and SMC- Sting -/- mice exhibited a reduction of SREBP2 activation and lipid content in macrophages and a reduction in atherosclerosis burden. Conclusions: Our findings indicated that DNA and cGAMP from damaged cells serve as a danger molecule that, by activating the cGAS-STING cytosolic DNA sensing signaling, promotes macrophage lipid biosynthesis and accumulation, contributing to atherosclerosis development.