Xiaoyong Tong1, Alok R Khandelwal2, Zhexue Qin3, Xiaojuan Wu4, Lili Chen5, Tetsuro Ago6, Junichi Sadoshima7, Richard A Cohen2. 1. Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China; Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: xiaoyongtong@cqu.edu.cn. 2. Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. 3. Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; Department of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. 4. Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China. 5. Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; Department of Cardiology, TongJi Hospital, Wuhan 430030, China. 6. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA. 7. Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
Abstract
UNLABELLED: Elevated levels of reactive oxygen species (ROS) in the vascular wall play a key role in the development of neointimal hyperplasia. Nox4-based NADPH oxidase is a major ROS generating enzyme in the vasculature, but its roles in neointimal hyperplasia remain unclear. OBJECTIVE: Our purpose was to investigate the role of smooth muscle cell (SMC) Nox4 in neointimal hyperplasia. APPROACH AND RESULTS: Mice overexpressing a human Nox4 mutant form, carrying a P437H dominant negative mutation (Nox4DN) and driven by SM22α promoter, to achieve specific expression in SMC, were generated in a FVB/N genetic background. After wire injury-induced endothelial denudation, Nox4DN had significantly decreased neointima formation compared with non-transgenic littermate controls (NTg). ROS production, serum-induced proliferation and migration, were significantly decreased in aortic SMCs isolated from Nox4DN compared with NTg. Both mRNA and protein levels of thrombospondin 1 (TSP1) were significantly downregulated in Nox4DN SMCs. Downregulation of TSP1 by siRNA decreased cell proliferation and migration in SMCs. Similar to Nox4DN, downregulation of Nox4 by siRNA significantly decreased TSP1 expression level, cell proliferation and migration in SMCs. CONCLUSIONS: Downregulation of smooth muscle Nox4 inhibits neointimal hyperplasia by suppressing TSP1, which in part can account for inhibition of SMC proliferation and migration.
UNLABELLED: Elevated levels of reactive oxygen species (ROS) in the vascular wall play a key role in the development of neointimal hyperplasia. Nox4-based NADPH oxidase is a major ROS generating enzyme in the vasculature, but its roles in neointimal hyperplasia remain unclear. OBJECTIVE: Our purpose was to investigate the role of smooth muscle cell (SMC) Nox4 in neointimal hyperplasia. APPROACH AND RESULTS:Mice overexpressing a humanNox4 mutant form, carrying a P437H dominant negative mutation (Nox4DN) and driven by SM22α promoter, to achieve specific expression in SMC, were generated in a FVB/N genetic background. After wire injury-induced endothelial denudation, Nox4DN had significantly decreased neointima formation compared with non-transgenic littermate controls (NTg). ROS production, serum-induced proliferation and migration, were significantly decreased in aortic SMCs isolated from Nox4DN compared with NTg. Both mRNA and protein levels of thrombospondin 1 (TSP1) were significantly downregulated in Nox4DN SMCs. Downregulation of TSP1 by siRNA decreased cell proliferation and migration in SMCs. Similar to Nox4DN, downregulation of Nox4 by siRNA significantly decreased TSP1 expression level, cell proliferation and migration in SMCs. CONCLUSIONS: Downregulation of smooth muscle Nox4 inhibits neointimal hyperplasia by suppressing TSP1, which in part can account for inhibition of SMC proliferation and migration.
Authors: Xiaoyong Tong; Xiuyun Hou; Christopher Wason; Tal Kopel; Richard A Cohen; Laura M Dember Journal: Am J Pathol Date: 2017-08-17 Impact factor: 4.307
Authors: Pingping Hu; Xiaojuan Wu; Alok R Khandelwal; Weimin Yu; Zaicheng Xu; Lili Chen; Jian Yang; Robert M Weisbrod; Kin Sing Stephen Lee; Francesca Seta; Bruce D Hammock; Richard A Cohen; Chunyu Zeng; Xiaoyong Tong Journal: Biochim Biophys Acta Mol Basis Dis Date: 2017-02-07 Impact factor: 5.187
Authors: Dimitry A Chistiakov; Alexandra A Melnichenko; Veronika A Myasoedova; Andrey V Grechko; Alexander N Orekhov Journal: Int J Mol Sci Date: 2017-07-17 Impact factor: 5.923