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      Plasma microfibrillar-associated protein 4 is not prognostic of emphysema progression but is associated with cardiovascular disease history and mortality in COPD patients

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          Abstract

          Chronic obstructive pulmonary disease (COPD) is characterised by chronic airflow limitation and inflammation of the airways and lung parenchyma. COPD is associated with many comorbidities, especially cardiovascular disease (CVD), which share similar risk factors with COPD [1].

          Abstract

          Circulating MFAP4 is a relevant biomarker to identify COPD patients at risk of death and cardiovascular comorbidity after smoking cessation http://ow.ly/6vnL30o8t1g

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          Most cited references13

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          Detection of novel biomarkers of liver cirrhosis by proteomic analysis.

          Hepatic cirrhosis is a life-threatening disease arising from different chronic liver disorders. One major cause for hepatic cirrhosis is chronic hepatitis C. Chronic hepatitis C is characterized by a highly variable clinical course, with at least 20% developing liver cirrhosis within 40 years. Only liver biopsy allows a reliable evaluation of the course of hepatitis C by grading inflammation and staging fibrosis, and thus serum biomarkers for hepatic fibrosis with high sensitivity and specificity are needed. To identify new candidate biomarkers for hepatic fibrosis, we performed a proteomic approach of microdissected cirrhotic septa and liver parenchyma cells. In cirrhotic septa, we detected an increasing expression of cell structure associated proteins, including actin, prolyl 4-hydroxylase, tropomyosin, calponin, transgelin, and human microfibril-associated protein 4 (MFAP-4). Tropomyosin, calponin, and transgelin reflect a contribution of activated stellate cells/myofibroblasts to chronic liver injury. The expression of tropomyosin, transgelin, and MFAP-4, an extracellular matrix associated protein, were further evaluated by immunohistochemistry. Tropomyosin and MFAP-4 demonstrated high serum levels in patients with hepatic cirrhosis of different causes. A quantitative analysis of MFAP-4 serum levels in a large number of patients showed MFAP-4 as novel candidate biomarker with high diagnostic accuracy for prediction of nondiseased liver versus cirrhosis [area under receiver operating characteristic curve (AUC) = 0.97, P < 0.0001] as well as stage 0 versus stage 4 fibrosis (AUC = 0.84, P < 0.0001), and stages 0 to 3 versus stage 4 fibrosis (AUC = 0.76, P < 0.0001).
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            Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation.

            MFAP4 (microfibrillar-associated protein 4) is an extracellular glycoprotein found in elastic fibers without a clearly defined role in elastic fiber assembly. In the present study, we characterized molecular interactions between MFAP4 and elastic fiber components. We established that MFAP4 primarily assembles into trimeric and hexameric structures of homodimers. Binding analysis revealed that MFAP4 specifically binds tropoelastin and fibrillin-1 and -2, as well as the elastin cross-linking amino acid desmosine, and that it co-localizes with fibrillin-1-positive fibers in vivo. Site-directed mutagenesis disclosed residues Phe(241) and Ser(203) in MFAP4 as being crucial for type I collagen, elastin, and tropoelastin binding. Furthermore, we found that MFAP4 actively promotes tropoelastin self-assembly. In conclusion, our data identify MFAP4 as a new ligand of microfibrils and tropoelastin involved in proper elastic fiber organization.
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              MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation.

              Arterial injury stimulates remodeling responses that, when excessive, lead to stenosis. These responses are influenced by integrin signaling in vascular smooth muscle cells (VSMCs). Microfibrillar-associated protein 4 (MFAP4) is an integrin ligand localized to extracellular matrix fibers in the vascular wall. The role of MFAP4 in vascular biology is unknown. We aimed to test the hypothesis that MFAP4 would enhance integrin-dependent VSMC activation.
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                Author and article information

                Journal
                ERJ Open Res
                ERJ Open Res
                ERJOR
                erjor
                ERJ Open Research
                European Respiratory Society
                2312-0541
                April 2019
                15 April 2019
                : 5
                : 2
                : 00021-2019
                Affiliations
                [1 ]Dept of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
                [2 ]Dept of Respiratory Medicine, Odense University Hospital, Odense, Denmark
                [3 ]GlaxoSmithKline R&D, Collegeville, PA, USA
                [4 ]Division of Infection, Immunity and Respiratory Medicine, The University of Manchester, Manchester Academic Health Science Centre, and Manchester NHS Foundation Trust, Manchester, UK
                Author notes
                Grith Lykke Sørensen, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winslows Vej 25.3, 5000 Odense C, Denmark. E-mail: glsorensen@ 123456health.sdu.dk
                Article
                00021-2019
                10.1183/23120541.00021-2019
                6469069
                31024964
                2bfbb1e6-34d2-4b50-bb28-1c842bf25221
                Copyright ©ERS 2019

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

                History
                : 21 January 2019
                : 24 February 2019
                Funding
                Funded by: The Danish Strategic Research Council
                Funded by: GlaxoSmithKline, open-funder-registry 10.13039/100004330;
                Funded by: NIHR Manchester Biomedical Research Centre
                Categories
                Original Research Letters
                1

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