In vitro and in vivo effects of SerpinA1 on the modulation of Transthyretin proteolysis
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/1822/79927 |
Resumo: | Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo. |
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In vitro and in vivo effects of SerpinA1 on the modulation of Transthyretin proteolysisCiências Médicas::Ciências da SaúdeTransthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.This research was funded by COMPETE 2020 of PT2020 through the European Regional Development Fund (ERDF), “NETDIAMOND—New Targets in DIAstolic heart failure: from coMOrbidities to persoNalizeD medicine” project financed by the European Structural and Investment Funds (ESIF), through the Programa Operacional Regional (POCI-01-0145-FEDER-016385) and HEALTHUNORTE: Setting-up biobanks and regenerative medicine strategies to boost research in cardiovascular, musculoskeletal, neurological, oncological, immunological, and infectious diseases, NORTE- 01-0145-FEDER-000039. FB was supported by FCT—Fundação para a Ciência e Tecnologia/MEC— Ministério da Educação e Ciência with a PhD fellowship (SFRH/BD/123674/2016).Multidisciplinary Digital Publishing InstituteUniversidade do MinhoBezerra, FilipaNiemietz, ChristophSchmidt, Hartmut H. J.Zibert, AndreeGuo, ShulingMonia, Brett P.Gonçalves, Paula Isabel MeiraSaraiva, Maria JoãoAlmeida, Maria Rosário2021-08-312021-08-31T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/1822/79927engBezerra, F.; Niemietz, C.; Schmidt, H.H.J.; Zibert, A.; Guo, S.; Monia, B.P.; Gonçalves, P.; Saraiva, M.J.; Almeida, M.R. In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis. Int. J. Mol. Sci. 2021, 22, 9488. https://doi.org/10.3390/ijms221794881422-006710.3390/ijms22179488https://www.mdpi.com/1422-0067/22/17/9488info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:13:22Zoai:repositorium.sdum.uminho.pt:1822/79927Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:05:26.732642Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
In vitro and in vivo effects of SerpinA1 on the modulation of Transthyretin proteolysis |
title |
In vitro and in vivo effects of SerpinA1 on the modulation of Transthyretin proteolysis |
spellingShingle |
In vitro and in vivo effects of SerpinA1 on the modulation of Transthyretin proteolysis Bezerra, Filipa Ciências Médicas::Ciências da Saúde |
title_short |
In vitro and in vivo effects of SerpinA1 on the modulation of Transthyretin proteolysis |
title_full |
In vitro and in vivo effects of SerpinA1 on the modulation of Transthyretin proteolysis |
title_fullStr |
In vitro and in vivo effects of SerpinA1 on the modulation of Transthyretin proteolysis |
title_full_unstemmed |
In vitro and in vivo effects of SerpinA1 on the modulation of Transthyretin proteolysis |
title_sort |
In vitro and in vivo effects of SerpinA1 on the modulation of Transthyretin proteolysis |
author |
Bezerra, Filipa |
author_facet |
Bezerra, Filipa Niemietz, Christoph Schmidt, Hartmut H. J. Zibert, Andree Guo, Shuling Monia, Brett P. Gonçalves, Paula Isabel Meira Saraiva, Maria João Almeida, Maria Rosário |
author_role |
author |
author2 |
Niemietz, Christoph Schmidt, Hartmut H. J. Zibert, Andree Guo, Shuling Monia, Brett P. Gonçalves, Paula Isabel Meira Saraiva, Maria João Almeida, Maria Rosário |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Bezerra, Filipa Niemietz, Christoph Schmidt, Hartmut H. J. Zibert, Andree Guo, Shuling Monia, Brett P. Gonçalves, Paula Isabel Meira Saraiva, Maria João Almeida, Maria Rosário |
dc.subject.por.fl_str_mv |
Ciências Médicas::Ciências da Saúde |
topic |
Ciências Médicas::Ciências da Saúde |
description |
Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-08-31 2021-08-31T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/1822/79927 |
url |
https://hdl.handle.net/1822/79927 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Bezerra, F.; Niemietz, C.; Schmidt, H.H.J.; Zibert, A.; Guo, S.; Monia, B.P.; Gonçalves, P.; Saraiva, M.J.; Almeida, M.R. In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis. Int. J. Mol. Sci. 2021, 22, 9488. https://doi.org/10.3390/ijms22179488 1422-0067 10.3390/ijms22179488 https://www.mdpi.com/1422-0067/22/17/9488 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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