Ji-Hyun Kim1, Yeon-Kyung Choi1, Ji-Yeon Do1, Young-Keun Choi1, Chae-Myeong Ha1, Sun Joo Lee1, Jae-Han Jeon1, Won-Kee Lee1, Hueng-Sik Choi1, Keun-Gyu Park2, In-Kyu Lee2. 1. From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.). 2. From the Department of Internal Medicine (J.-H.K., Y.-K.C., Y.-K.C., S.J.L., J.-H.J., K.-G.P., I.-K.L.), Research Institute of Aging and Metabolism (J.-H.K., S.J.L., K.-G.P., I.-K.L.), and BK21 Plus KNU Biomedical Convergence Program (C.-M.H., I.-K.L.), Kyungpook National University School of Medicine, Daegu, South Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease (Y.-K.C., J.-Y.D., Y.-K.C., J.-H.J., K.-G.P., I.-K.L.), Department of Biomedical Science, Graduate School of Medicine (C.-M.H., K.-G.P., I.-K.L.), Department of Ophthalmology, School of Medicine (J.-Y.D.), and Biomedical Research Institute, School of Medicine (W.-K.L.), Kyungpook National University, Daegu, South Korea; and National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea (H.-S.C.). leei@knu.ac.kr kpark@knu.ac.kr.
Abstract
OBJECTIVE: Vascular calcification which refers to ectopic mineralization in vascular cells is associated with several conditions, such as chronic kidney disease, atherosclerosis, and diabetes mellitus. Estrogen-related receptor (ERR)γ is a member of the orphan nuclear receptor superfamily, which plays diverse roles in regulating homeostatic and metabolic processes. However, the role of ERRγ in vascular calcification has not been investigated to date. The aim of the present study was to examine the role of ERRγ in vascular calcification. APPROACH AND RESULTS: Vascular calcification was induced by treating rat aortic vascular smooth muscle cells with calcification medium. ERRγ expression in vascular smooth muscle cells was induced during calcification medium-induced vascular calcification. Adenovirus-mediated overexpression of ERRγ in vascular smooth muscle cells resulted in the upregulation of the expression of osteogenic genes, including runt-related transcription factor 2, osteopontin, and Msx2, and the downregulation of α-smooth muscle actin. Adenovirus-mediated overexpression of ERRγ induced bone morphogenetic protein 2 (BMP2) expression, leading to increased phosphorylation of the intracellular BMP2 effector proteins SMAD1/5/8. Collectively, these data suggested that ERRγ promotes dedifferentiation of vascular smooth muscle cells to an osteogenic phenotype during the vascular calcification process. Inhibition of endogenous ERRγ expression or activity using a specific siRNA or the selective inverse agonist GSK5182 attenuated vascular calcification and osteogenic gene expression in vitro and in vivo. CONCLUSIONS: The present results indicate that ERRγ plays a key role in vascular calcification by upregulating the BMP2 signaling pathway, suggesting that inhibition of ERRγ is a potential therapeutic strategy for the prevention of vascular calcification.
OBJECTIVE:Vascular calcification which refers to ectopic mineralization in vascular cells is associated with several conditions, such as chronic kidney disease, atherosclerosis, and diabetes mellitus. Estrogen-related receptor (ERR)γ is a member of the orphan nuclear receptor superfamily, which plays diverse roles in regulating homeostatic and metabolic processes. However, the role of ERRγ in vascular calcification has not been investigated to date. The aim of the present study was to examine the role of ERRγ in vascular calcification. APPROACH AND RESULTS:Vascular calcification was induced by treating rat aortic vascular smooth muscle cells with calcification medium. ERRγ expression in vascular smooth muscle cells was induced during calcification medium-induced vascular calcification. Adenovirus-mediated overexpression of ERRγ in vascular smooth muscle cells resulted in the upregulation of the expression of osteogenic genes, including runt-related transcription factor 2, osteopontin, and Msx2, and the downregulation of α-smooth muscle actin. Adenovirus-mediated overexpression of ERRγ induced bone morphogenetic protein 2 (BMP2) expression, leading to increased phosphorylation of the intracellular BMP2 effector proteins SMAD1/5/8. Collectively, these data suggested that ERRγ promotes dedifferentiation of vascular smooth muscle cells to an osteogenic phenotype during the vascular calcification process. Inhibition of endogenous ERRγ expression or activity using a specific siRNA or the selective inverse agonist GSK5182attenuated vascular calcification and osteogenic gene expression in vitro and in vivo. CONCLUSIONS: The present results indicate that ERRγ plays a key role in vascular calcification by upregulating the BMP2 signaling pathway, suggesting that inhibition of ERRγ is a potential therapeutic strategy for the prevention of vascular calcification.
Authors: Cavin K Ward-Caviness; Lucas M Neas; Colette Blach; Carol S Haynes; Karen LaRocque-Abramson; Elizabeth Grass; Elaine Dowdy; Robert B Devlin; David Diaz-Sanchez; Wayne E Cascio; Marie Lynn Miranda; Simon G Gregory; Svati H Shah; William E Kraus; Elizabeth R Hauser Journal: PLoS One Date: 2016-04-15 Impact factor: 3.240
Authors: Jin Li; Carmen Carrillo García; Tamara Riedt; Maria Brandes; Sabrina Szczepanski; Peter Brossart; Wolfgang Wagner; Viktor Janzen Journal: Sci Rep Date: 2018-02-12 Impact factor: 4.379