Chen Pengyuan, Hong Wanzi, Chen Ziying, Gordillo-Martinez Flora, Wang Siying, Fan Hualin, Liu Yuanhui, Dai Yining, Wang Bo, Jiang Lei, Yu Hongjiao, He PengCheng
Department of Cardiology, Guangdong Provincial People's Hospital's Nanhai Hospital, The Second Hospital of Nanhai District Foshan City, Foshan, China.
Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Front Physiol. 2022 Feb 28;13:755371. doi: 10.3389/fphys.2022.755371. eCollection 2022.
Vascular calcification is a common clinical complication of chronic kidney disease (CKD), atherosclerosis (AS), and diabetes, which is associated with increased cardiovascular morbidity and mortality in patients. The transdifferentiation of vascular smooth muscle cells (VSMCs) to an osteochondrogenic phenotype is a crucial step during vascular calcification. The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) plays an important role in regulating cell proliferation and differentiation, but whether it regulates the calcification of arteries and VSMCs remains unclear. Therefore, this study aims to understand the role of C/EBPα in the regulation of vascular calcification.
Both mRNA and protein expression levels of C/EBPα were significantly increased in calcified arteries from mice treated with a high dose of vitamin D3 (vD3). Upregulation of C/EBPα was also observed in the high phosphate- and calcium-induced VSMC calcification process. The siRNA-mediated knockdown of C/EBPα significantly attenuated VSMC calcification . Moreover, C/EBPα depletion in VSMCs significantly reduced the mRNA expression of the osteochondrogenic genes, e.g., sex-determining region Y-box 9 (Sox9). C/EBPα overexpression can induce SOX9 overexpression. Similar changes in the protein expression of SOX9 were also observed in VSMCs after C/EBPα depletion or overexpression. In addition, silencing of Sox9 expression significantly inhibited the phosphate- and calcium-induced VSMC calcification .
Findings in this study indicate that C/EBPα is a key regulator of the osteochondrogenic transdifferentiation of VSMCs and vascular calcification, which may represent a novel therapeutic target for vascular calcification.
血管钙化是慢性肾脏病（CKD）、动脉粥样硬化（AS）和糖尿病常见的临床并发症，与患者心血管发病率和死亡率增加相关。血管平滑肌细胞（VSMC）向成骨软骨细胞表型的转分化是血管钙化过程中的关键步骤。转录因子CCAAT/增强子结合蛋白α（C/EBPα）在调节细胞增殖和分化中起重要作用，但它是否调节动脉和VSMC的钙化尚不清楚。因此，本研究旨在了解C/EBPα在血管钙化调节中的作用。
在高剂量维生素D3（vD3）处理的小鼠钙化动脉中，C/EBPα的mRNA和蛋白表达水平均显著增加。在高磷和钙诱导的VSMC钙化过程中也观察到C/EBPα的上调。siRNA介导的C/EBPα敲低显著减弱了VSMC钙化。此外，VSMC中C/EBPα的缺失显著降低了成骨软骨细胞基因（如性别决定区Y盒9，Sox9）的mRNA表达。C/EBPα过表达可诱导SOX9过表达。在C/EBPα缺失或过表达后的VSMC中，也观察到SOX9蛋白表达的类似变化。此外，Sox9表达的沉默显著抑制了磷和钙诱导的VSMC钙化。
本研究结果表明，C/EBPα是VSMC成骨软骨细胞转分化和血管钙化的关键调节因子，这可能代表血管钙化的一个新的治疗靶点。
