Abstract
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/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 ResultsBoth 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.ConclusionFindings 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.
Highlights
Cardiovascular disease is the leading cause of death globally, and vascular calcification is the basic pathologic change
The osteogenic transformation of vascular smooth muscle cells (VSMCs) is the characteristic change during vascular calcification process, with decreased expression of contractile proteins like SMA, whereas increased expression of osteogenic genes, such as Runt-related transcription factor 2 (Runx2), bone morphogenetic protein-2 (Bmp2), osteopontin (OPN), alkaline phosphatase (ALP), and sex-determining region Y-box 9 (Sox9) (Shanahan et al, 2011)
The mRNA expression genes, such as Runx2 (5.7-fold, p = 0.035), Alpl (1.9fold, p < 0.001), Opn (2.9-fold, p < 0.01), Bmp2 (4.0-fold, p < 0.01), and Sox9 (2.4-fold, p < 0.01), were significantly increased in vascular calcification murine model, while the mRNA expression of Sma was significantly decreased by 90% (p < 0.01)
Summary
Cardiovascular disease is the leading cause of death globally, and vascular calcification is the basic pathologic change. Vascular calcification is a pathologic change of the vascular wall resulting from mineral deposition which can increase the risk of cardiovascular disease (CVD), stroke, and atherosclerosis (AS) (Nicoll and Henein, 2014). The change from contractile to chondrogenic phenotype of vascular smooth muscle cells (VSMCs) is known to play a key role in vascular calcification. Similar to osteogenic differentiation of bone, vascular calcification is characterized by some key osteogenic regulators. The osteogenic transformation of VSMCs is the characteristic change during vascular calcification process, with decreased expression of contractile proteins like SMA, whereas increased expression of osteogenic genes, such as Runt-related transcription factor 2 (Runx2), bone morphogenetic protein-2 (Bmp2), osteopontin (OPN), alkaline phosphatase (ALP), and sex-determining region Y-box 9 (Sox9) (Shanahan et al, 2011)
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