Succinate induces histone succinylation to accelerate arterial calcification by activating FRA1/CREB3L2 axis

Background Arterial calcification is a strong predictor of morbidity and mortality in cardiovascular diseases. Osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) has been recognized as the crucial pathological basis for arterial calcification. Succinate plays critical roles in a variety of cardiovascular diseases. However, its role in arterial calcification and the underlying mechanisms remain unexplored. Purpose We aimed to investigate the role of succinate in the pathogenesis of arterial calcification and its potential clinical relevance. Methods To investigate the clinical relevance of succinate metabolism and arterial calcification, we performed LC-MS/MS detection in plasma samples from patients with arterial calcification and healthy controls. Then we generated arterial calcification models to explore the biological roles of succinate in arterial calcification. Histone succinylation was also studied in VSMCs treated with high phosphate. Cleavage Under Targets and Tagmentation analysis was performed to determine the transcriptional profile of histone succinylation in VSMCs under phosphate treatment. We integrated Cleavage Under Targets and Tagmentation analysis and RNA-seq data to further investigate the target genes regulated by histone succinylation. Results High succinate levels were positively correlated with total Agatston scores in patients with arterial calcification. Moreover, succinate supplementation accelerated arterial calcification both in vitro and in vivo. Histone succinylation (H3K79su) was increased in phosphate-stimulated VSMCs(Figure 1). Mechanistically, H3K79su promoted the transcriptional activation of cAMP responsive element binding protein 3 like 2 (CREB3L2). Consistently, inhibition of CREB3L2 attenuated calcium deposition in a mouse model of arterial calcification. Furthermore, FOS-like 1(FRA1) was enriched in CREB3L2 promoter regions, and inhibition of FRA1 suppressed arterial calcification by disrupting the H3K79su/CREB3L2 pathway(Figure 2). Conclusion Our findings reveal that succinate-mediated histone succinylation constitutes a novel metabolome-epigenome crosstalk signaling cascade involved in the pathogenesis of arterial calcification. Furthermore, inhibition of CREB3L2 or FRA1 may represent a potential strategy for the treatment and prevention of arterial calcification.