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- Title
APE1/Ref-1 Inhibits Phosphate-Induced Calcification and Osteoblastic Phenotype Changes in Vascular Smooth Muscle Cells.
- Authors
Ki Mo Lee; Eun Ok Lee; Yu Ran Lee; Hee Kyoung Joo; Myoung Soo Park; Cuk-Seong Kim; Sunga Choi; Jin-Ok Jeong; Byeong Hwa Jeon
- 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.
- Subjects
CALCIFICATION; VASCULAR smooth muscle physiology; OSTEOBLASTS; GENETIC overexpression; APURINIC acid; LACTATE dehydrogenase; ALKALINE phosphatase; OXIDATIVE stress; PREVENTION; PHYSIOLOGY
- Publication
International Journal of Molecular Sciences, 2017, Vol 18, Issue 10, p2053
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms18102053