Research Paper Volume 12, Issue 21 pp 21220—21235
Cyclooxygenase-2/sclerostin mediates TGF-β1-induced calcification in vascular smooth muscle cells and rats undergoing renal failure
- 1 Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
- 2 Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- 3 Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing 400016, China
- 4 Department of Orthopedic, Children Hospital of Chongqing Medical University, Chongqing 400014, China
Received: March 11, 2020 Accepted: July 14, 2020 Published: November 6, 2020
https://doi.org/10.18632/aging.103827How to Cite
Copyright: © 2020 He et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
In this study, we studied the effect and possible mechanism of TGF-β1 on vascular calcification. We found that the serum levels of TGF-β1 and cycloxygenase-2 (COX-2) were significantly increased in patients with chronic kidney disease. Phosphate up regulated TGF-β1 in vascular smooth muscle cells (VSMCs). TGF-β1 decreased the markers of VSMCs, but increased osteogenic markers and calcification in aortic segments. The phosphate-induced osteogenic markers were reduced by the TGFβR I inhibitor (LY364947), which also attenuated the potential of phosphate to reduce VSMC markers in VSMCs. Both phosphate and TGF-β1 increased the protein level of β-catenin, which was partially mitigated by LY364947. TGF-β1 decreased sclerostin, and exogenous sclerostin decreased the mineralization induced by TGF-β1. LY364947 reduced the phosphate and TGF-β1 induced COX-2. Meanwhile, the effects of TGF-β1 on osteogenic markers, β-catenin, and sclerostin, were partially reversed by the COX-2 inhibitor. Mechanistically, we found that p-Smad2/3 and p-CREB were both enriched at the promoter regions of sclerostin and β-catenin. TGF-β1 and COX-2 were significantly elevated in serum and aorta of rats undergoing renal failure. Therapeutic administration of meloxicam effectively ameliorated the renal lesion. Our results suggested that COX-2 may mediate the effect of TGF-β1 on vascular calcification through down-regulating sclerostin in VMSCs.