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BMP9/COX-2 axial mediates high phosphate-induced calcification in vascular smooth muscle cells via Wnt/β-catenin pathway.

Authors
  • He, Fang1, 2
  • Wang, Han2, 3
  • Ren, Wen-Yan2, 3
  • Ma, Yan2, 3
  • Liao, Yun-Peng2, 3
  • Zhu, Jia-Hui2, 3
  • Cui, Jin4
  • Deng, Zhong-Liang5
  • Su, Yu-Xi6
  • Gan, Hua1
  • He, Bai-Cheng2, 3
  • 1 Department of Nephrology, First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China. , (China)
  • 2 Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, People's Republic of China. , (China)
  • 3 Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, People's Republic of China. , (China)
  • 4 Infectious Disease Laboratory of Chongqing Medical University, Chongqing, People's Republic of China. , (China)
  • 5 Department of Orthorpedic, Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China. , (China)
  • 6 Department of Orthorpedic, Children Hospital of Chongqing Medical University, Chongqing, People's Republic of China. , (China)
Type
Published Article
Journal
Journal of Cellular Biochemistry
Publisher
Wiley (John Wiley & Sons)
Publication Date
Mar 01, 2018
Volume
119
Issue
3
Pages
2851–2863
Identifiers
DOI: 10.1002/jcb.26460
PMID: 29073723
Source
Medline
Keywords
License
Unknown

Abstract

Vascular calcification is a notable risk factor for cardiovascular system. High phosphate can induce calcification in vascular smooth muscle cells (VSMCs), but the detail mechanism underlying this process remains unclear. In the present study, we determined the relationship between high phosphate and bone morphogenetic protein 9 (BMP9) in VSMCs, the effect of BMP9 on calcification in VSMCs and the effect of COX-2 on BMP9 induced calcification in VSMCs, as well as the possible mechanism underlying this biological process. We found that high phosphate obviously up-regulates the expression of BMP9 in VSMCs. Over-expression of BMP9 decreases the level of alpha-smooth muscle cell actin (α-SMA) apparently, but increases the level of Runx-2, Dlx-5, and ALP in VSMCs. Meanwhile, BMP9 increases the level of OPN and OCN, promotes mineralization in VSMCs and induces calcification in thoracic aorta. High phosphate and over-expression of BMP9 increases the level of COX-2. Over-expression of COX-2 enhances the inhibitory effect of BMP9 on α-SAM and increases the level of OPN and OCN induced by BMP9. However, inhibition of COX-2 decreases the BMP9-induced calcification in VSMCs and thoracic aorta. For mechanism, we found that high phosphate or BMP9 increases the level of β-catenin and p-GSK3β in VSMCs, but no substantial effect on GSK3β. However, COX-2 inhibitor decreases the expression of β-catenin induced by BMP9. Our findings indicated that BMP9 is involved in the phosphate-induced calcification in VSMCs and COX-2 partly mediates the BMP9-induced calcification in VSMCs through activating Wnt/β-catenin pathway.

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