The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts.

Autor: Rypdal KB; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Building 7, 4th floor, Kirkeveien 166, 0407, Oslo, Norway.; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway., Erusappan PM; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Building 7, 4th floor, Kirkeveien 166, 0407, Oslo, Norway.; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway., Melleby AO; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Building 7, 4th floor, Kirkeveien 166, 0407, Oslo, Norway.; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.; Section of Physiology, Department of Molecular Medicine, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway., Seifert DE; Department of Biomedical Engineering, Cleveland Clinic Lerner Institute, Cleveland, OH, USA., Palmero S; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Building 7, 4th floor, Kirkeveien 166, 0407, Oslo, Norway.; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway., Strand ME; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Building 7, 4th floor, Kirkeveien 166, 0407, Oslo, Norway.; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway., Tønnessen T; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Building 7, 4th floor, Kirkeveien 166, 0407, Oslo, Norway.; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.; Department of Cardiothoracic Surgery, Oslo University Hospital Ullevaal, Oslo, Norway., Dahl CP; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway., Almaas V; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway., Hubmacher D; Orthopaedic Research Laboratories, Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Apte SS; Department of Biomedical Engineering, Cleveland Clinic Lerner Institute, Cleveland, OH, USA., Christensen G; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Building 7, 4th floor, Kirkeveien 166, 0407, Oslo, Norway.; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway., Lunde IG; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Building 7, 4th floor, Kirkeveien 166, 0407, Oslo, Norway. i.g.lunde@medisin.uio.no.; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway. i.g.lunde@medisin.uio.no.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Oct 05; Vol. 11 (1), pp. 19757. Date of Electronic Publication: 2021 Oct 05.
DOI: 10.1038/s41598-021-99032-2
Abstrakt: Fibrosis accompanies most heart diseases and is associated with adverse patient outcomes. Transforming growth factor (TGF)β drives extracellular matrix remodelling and fibrosis in the failing heart. Some members of the ADAMTSL (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motifs-like) family of secreted glycoproteins bind to matrix microfibrils, and although their function in the heart remains largely unknown, they are suggested to regulate TGFβ activity. The aims of this study were to determine ADAMTSL2 levels in failing hearts, and to elucidate the role of ADAMTSL2 in fibrosis using cultured human cardiac fibroblasts (CFBs). Cardiac ADAMTSL2 mRNA was robustly increased in human and experimental heart failure, and mainly expressed by fibroblasts. Over-expression and treatment with extracellular ADAMTSL2 in human CFBs led to reduced TGFβ production and signalling. Increased ADAMTSL2 attenuated myofibroblast differentiation, with reduced expression of the signature molecules α-smooth muscle actin and osteopontin. Finally, ADAMTSL2 mitigated the pro-fibrotic CFB phenotypes, proliferation, migration and contractility. In conclusion, the extracellular matrix-localized glycoprotein ADAMTSL2 was upregulated in fibrotic and failing hearts of patients and mice. We identified ADAMTSL2 as a negative regulator of TGFβ in human cardiac fibroblasts, inhibiting myofibroblast differentiation and pro-fibrotic properties.
(© 2021. The Author(s).)
Databáze: MEDLINE
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