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Int. J. Mol. Sci. 2017, 18(10), 2053; doi:10.3390/ijms18102053

APE1/Ref-1 Inhibits Phosphate-Induced Calcification and Osteoblastic Phenotype Changes in Vascular Smooth Muscle Cells

1
Research Institute of Medical Sciences, Department of Physiology, School of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Korea
2
Division of Cardiology, Department of Internal Medicine, Chungnam National University, Daejeon 35015, Korea
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 28 August 2017 / Revised: 12 September 2017 / Accepted: 19 September 2017 / Published: 25 September 2017
(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)
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Abstract

Vascular calcification plays a role in the pathogenesis of atherosclerosis, diabetes, and chronic kidney disease; however, the role of apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) in inorganic phosphate (Pi)-induced vascular smooth muscle cell (VSMC) calcification remains unknown. In this study, we investigated the possible role of APE1/Ref-1 in Pi-induced VSMC calcification. We observed that Pi decreased endogenous APE1/Ref-1 expression and promoter activity in VSMCs, and that adenoviral overexpression of APE1/Ref-1 inhibited Pi-induced calcification in VSMCs and in an ex vivo organ culture of a rat aorta. However, a redox mutant of APE1/Ref-1(C65A/C93A) did not reduce Pi-induced calcification in VSMCs, suggesting APE1/Ref-1-mediated redox function against vascular calcification. Additionally, APE1/Ref-1 overexpression inhibited Pi-induced intracellular and mitochondrial reactive oxygen species production, and APE1/Ref-1 overexpression resulted in decreased Pi-induced lactate dehydrogenase activity, pro-apoptotic Bax levels, and increased anti-apoptotic Bcl-2 protein levels. Furthermore, APE1/Ref-1 inhibited Pi-induced osteoblastic differentiation associated with alkaline phosphatase activity and inhibited Pi-exposure-induced loss of the smooth muscle phenotype. Our findings provided valuable insights into the redox function of APE1/Ref-1 in preventing Pi-induced VSMC calcification by inhibiting oxidative stress and osteoblastic differentiation, resulting in prevention of altered osteoblastic phenotypes in VSMCs. View Full-Text
Keywords: APE1/Ref-1; inorganic phosphate; vascular smooth muscle cells; vascular calcification APE1/Ref-1; inorganic phosphate; vascular smooth muscle cells; vascular calcification
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lee, K.M.; Lee, E.O.; Lee, Y.R.; Joo, H.K.; Park, M.S.; Kim, C.-S.; Choi, S.; Jeong, J.-O.; Jeon, B.H. APE1/Ref-1 Inhibits Phosphate-Induced Calcification and Osteoblastic Phenotype Changes in Vascular Smooth Muscle Cells. Int. J. Mol. Sci. 2017, 18, 2053.

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