Role of smooth muscle Nox4-based NADPH oxidase in neointimal hyperplasia |
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| Institution: | 1. Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China;2. Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA;3. Department of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China;4. Department of Cardiology, TongJi Hospital, Wuhan 430030, China;5. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan;6. Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA;1. Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, The Netherlands;2. Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany;3. National Heart and Lung Institute, Imperial College London, London, UK;1. Laboratory of Molecular and Cellular Cardiology, Dep. of Clinical Biochemistry and Pharmacology, Odense University Hospital, Winsloewparken 21 3rd, 5000 Odense C, Denmark;2. Clinical Institute, University of Southern Denmark, 5000 Odense C, Denmark;3. Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense C, Denmark;1. Young Researchers and Elite Club, Central Tehran Branch, Islamic Azad University, Tehran, Iran;2. Young Researchers and Elite Club, Shahr-e-Rey Branch, Islamic Azad University, Tehran, Iran;3. Department of Chemistry, P. O. Box 305070, University of North Texas, Denton, TX 76203-5070, USA |
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| Abstract: | 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.ObjectiveOur purpose was to investigate the role of smooth muscle cell (SMC) Nox4 in neointimal hyperplasia.Approach and resultsMice 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.ConclusionsDownregulation of smooth muscle Nox4 inhibits neointimal hyperplasia by suppressing TSP1, which in part can account for inhibition of SMC proliferation and migration. |
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