Reactive Oxygen-Forming Nox5 Links Vascular Smooth Muscle Cell Phenotypic Switching and Extracellular Vesicle-Mediated Vascular Calcification
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- Malgorzata Furmanik
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Martijn Chatrou
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Rick van Gorp
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Asim Akbulut
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Brecht Willems
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Harald Schmidt
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Guillaume van Eys
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Marie-Luce Bochaton-Piallat
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Diane Proudfoot
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Erik Biessen
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Ulf Hedin
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Ljubica Perisic
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Barend Mees
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Catherine Shanahan
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Chris Reutelingsperger
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
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- Leon Schurgers
- From the Biochemistry (M.F., M.C., R.v.G., A.A., B.W., G.v.E., C.R., L.S.) and Pathology (E.B.), Cardiovascular Research Institute Maastricht, Pharmacology and Personalised Medicine, Faculty of Health, Medicine and Life Sciences (H.S.), Maastricht University, The Netherlands; Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland (M.-L.B.-P.); Signalling Programme, Babraham Institute, Cambridge, United Kingdom (D.P.); Molecular Medicine and Surgery, Vascular Surgery...
抄録
<jats:sec> <jats:title>Rationale:</jats:title> <jats:p>Vascular calcification, the formation of calcium phosphate crystals in the vessel wall, is mediated by vascular smooth muscle cells (VSMCs). However, the underlying molecular mechanisms remain elusive, precluding mechanism-based therapies.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p>Phenotypic switching denotes a loss of contractile proteins and an increase in migration and proliferation, whereby VSMCs are termed synthetic. We examined how VSMC phenotypic switching influences vascular calcification and the possible role of the uniquely calcium-dependent reactive oxygen species (ROS)-forming Nox5 (NADPH oxidase 5).</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results:</jats:title> <jats:p> In vitro cultures of synthetic VSMCs showed decreased expression of contractile markers CNN-1 (calponin 1), α-SMA (α-smooth muscle actin), and SM22-α (smooth muscle protein 22α) and an increase in synthetic marker S100A4 (S100 calcium binding protein A4) compared with contractile VSMCs. This was associated with increased calcification of synthetic cells in response to high extracellular Ca <jats:sup>2+</jats:sup> . Phenotypic switching was accompanied by increased levels of ROS and Ca <jats:sup>2+</jats:sup> -dependent Nox5 in synthetic VSMCs. Nox5 itself regulated VSMC phenotype as siRNA knockdown of Nox5 increased contractile marker expression and decreased calcification, while overexpression of Nox5 decreased contractile marker expression. ROS production in synthetic VSMCs was cytosolic Ca <jats:sup>2+</jats:sup> -dependent, in line with it being mediated by Nox5. Treatment of VSMCs with Ca <jats:sup>2+</jats:sup> loaded extracellular vesicles (EVs) lead to an increase in cytosolic Ca <jats:sup>2+</jats:sup> . Inhibiting EV endocytosis with dynasore blocked the increase in cytosolic Ca <jats:sup>2+</jats:sup> and VSMC calcification. Increased ROS production resulted in increased EV release and decreased phagocytosis by VSMCs. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p> We show here that contractile VSMCs are resistant to calcification and identify Nox5 as a key regulator of VSMC phenotypic switching. Additionally, we describe a new mechanism of Ca <jats:sup>2+</jats:sup> uptake via EVs and show that Ca <jats:sup>2+</jats:sup> induces ROS production in VSMCs via Nox5. ROS production is required for release of EVs, which promote calcification. Identifying molecular pathways that control Nox5 and VSMC-derived EVs provides potential targets to modulate vascular remodeling and calcification in the context of mineral imbalance. </jats:p> </jats:sec> <jats:sec> <jats:title>Graphic Abstract:</jats:title> <jats:p> A <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.316388">graphic abstract</jats:ext-link> is available for this article. </jats:p> </jats:sec>
収録刊行物
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- Circulation Research
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Circulation Research 127 (7), 911-927, 2020-09-11
Ovid Technologies (Wolters Kluwer Health)