Orphan Nuclear Receptor NR4A3 Promotes Vascular Calcification via Histone Lactylation

作者：Wenqi Ma, Kangni Jia, Haomai Cheng, Xu Hong, Zhigang Li, Hang Zhang, Hongyang Xie, Hang Sun, Lei Yi, Zhiyong Chen, Sheng‐Zhong Duan, Motoaki Sano, Keiichi Fukuda, Lin Lu, Fei Gao, Ruiyan Zhang, Xiaoxiang Yan · 发表于：Circulation Research · 年份：2024 · DOI：10.1161/circresaha.123.323699 · 被引用次数：99 · 研究领域：Nuclear Receptors and Signaling、Nerve injury and regeneration、Parkinson's Disease Mechanisms and Treatments

BACKGROUND: Medial arterial calcification is a chronic systemic vascular disorder distinct from atherosclerosis and is commonly observed in patients with chronic kidney disease, diabetes, and aging individuals. We previously showed that NR4A3 (nuclear receptor subfamily 4 group A member 3), an orphan nuclear receptor, is a key regulator in apo (apolipoprotein) A-IV-induced atherosclerosis progression; however, its role in vascular calcification is poorly understood. METHODS: We generated NR4A3 −/− mice and 2 different types of medial arterial calcification models to investigate the biological roles of NR4A3 in vascular calcification. RNA-seq was performed to determine the transcriptional profile of NR4A3 −/− vascular smooth muscle cells under β-glycerophosphate treatment. We integrated Cleavage Under Targets and Tagmentation analysis and RNA-seq data to further investigate the gene regulatory mechanisms of NR4A3 in arterial calcification and target genes regulated by histone lactylation. RESULTS: NR4A3 expression was upregulated in calcified aortic tissues from chronic kidney disease mice, 1,25(OH) 2 VitD 3 overload–induced mice, and human calcified aorta. NR4A3 deficiency preserved the vascular smooth muscle cell contractile phenotype, inhibited osteoblast differentiation-related gene expression, and reduced calcium deposition in the vasculature. Further, NR4A3 deficiency lowered the glycolytic rate and lactate production during the calcification process and decreased histon...