CCAAT/Enhancer-Binding Protein Alpha Is a Novel Regulator of Vascular Smooth Muscle Cell Osteochondrogenic Transition and Vascular Calcification

AimsVascular 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/EBP_) 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/EBP_ in the regulation of vascular calcification.Methods and ResultsBoth mRNA and protein expression levels of C/EBP_ were significantly increased in calcified arteries from mice treated with a high dose of vitamin D3 (vD3). Upregulation of C/EBP_ was also observed in the high phosphate- and calcium-induced VSMC calcification process. The siRNA-mediated knockdown of C/EBP_ significantly attenuated VSMC calcification in vitro. Moreover, C/EBP_ depletion in VSMCs significantly reduced the mRNA expression of the osteochondrogenic genes, e.g., sex-determining region Y-box 9 (Sox9). C/EBP_ overexpression can induce SOX9 overexpression. Similar changes in the protein expression of SOX9 were also observed in VSMCs after C/EBP_ depletion or overexpression. In addition, silencing of Sox9 expression significantly inhibited the phosphate- and calcium-induced VSMC calcification in vitro.ConclusionFindings in this study indicate that C/EBP_ is a key regulator of the osteochondrogenic transdifferentiation of VSMCs and vascular calcification, which may represent a novel therapeutic target for vascular calcification.