ABSTRACT
Aims:
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.
Methods and
Results:
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
in vitro. 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
in vitro.
Conclusion:
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.
