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

Abstract 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 thrombospo...

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Autores principales:	Karoline B. Rypdal, Pugazendhi M. Erusappan, A. Olav Melleby, Deborah E. Seifert, Sheryl Palmero, Mari E. Strand, Theis Tønnessen, Christen P. Dahl, Vibeke Almaas, Dirk Hubmacher, Suneel S. Apte, Geir Christensen, Ida G. Lunde
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ce2aba904d844c0083d6fbfea2ad66f8
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spelling	oai:doaj.org-article:ce2aba904d844c0083d6fbfea2ad66f82021-12-02T19:16:14ZThe extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts10.1038/s41598-021-99032-22045-2322https://doaj.org/article/ce2aba904d844c0083d6fbfea2ad66f82021-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-99032-2https://doaj.org/toc/2045-2322Abstract 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.Karoline B. RypdalPugazendhi M. ErusappanA. Olav MellebyDeborah E. SeifertSheryl PalmeroMari E. StrandTheis TønnessenChristen P. DahlVibeke AlmaasDirk HubmacherSuneel S. ApteGeir ChristensenIda G. LundeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Karoline B. Rypdal Pugazendhi M. Erusappan A. Olav Melleby Deborah E. Seifert Sheryl Palmero Mari E. Strand Theis Tønnessen Christen P. Dahl Vibeke Almaas Dirk Hubmacher Suneel S. Apte Geir Christensen Ida G. Lunde The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts
description	Abstract 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.
format	article
author	Karoline B. Rypdal Pugazendhi M. Erusappan A. Olav Melleby Deborah E. Seifert Sheryl Palmero Mari E. Strand Theis Tønnessen Christen P. Dahl Vibeke Almaas Dirk Hubmacher Suneel S. Apte Geir Christensen Ida G. Lunde
author_facet	Karoline B. Rypdal Pugazendhi M. Erusappan A. Olav Melleby Deborah E. Seifert Sheryl Palmero Mari E. Strand Theis Tønnessen Christen P. Dahl Vibeke Almaas Dirk Hubmacher Suneel S. Apte Geir Christensen Ida G. Lunde
author_sort	Karoline B. Rypdal
title	The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts
title_short	The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts
title_full	The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts
title_fullStr	The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts
title_full_unstemmed	The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts
title_sort	extracellular matrix glycoprotein adamtsl2 is increased in heart failure and inhibits tgfβ signalling in cardiac fibroblasts
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ce2aba904d844c0083d6fbfea2ad66f8
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The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts

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