Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation

Abstract Plasminogen activator inhibitor-1 (PAI-1) is known to protect mice against cardiac fibrosis. It has been speculated that PAI-1 may regulate cardiac fibrosis by inactivating urokinase-type plasminogen activator (uPA) and ultimately plasmin (Pm) generation. However, the in vivo role of PAI-1...

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Autores principales:	Kamlesh K. Gupta, Deborah L. Donahue, Mayra J. Sandoval-Cooper, Francis J. Castellino, Victoria A. Ploplis
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b61808fa7a1343d587e54e6e25fbad0a
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spelling	oai:doaj.org-article:b61808fa7a1343d587e54e6e25fbad0a2021-12-02T16:06:44ZPlasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation10.1038/s41598-017-00418-y2045-2322https://doaj.org/article/b61808fa7a1343d587e54e6e25fbad0a2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00418-yhttps://doaj.org/toc/2045-2322Abstract Plasminogen activator inhibitor-1 (PAI-1) is known to protect mice against cardiac fibrosis. It has been speculated that PAI-1 may regulate cardiac fibrosis by inactivating urokinase-type plasminogen activator (uPA) and ultimately plasmin (Pm) generation. However, the in vivo role of PAI-1 in inactivating uPA and limiting the generation of Pm during cardiac fibrosis remains to be established. The objective of this study was to determine if the cardioprotective effect of PAI-1 is mediated through its ability to directly regulate urokinase -mediated activation of plasminogen (Pg). An Angiotensin II (AngII)-aldosterone (Ald) infusion mouse model of hypertension was utilised in this study. Four weeks after AngII-Ald infusion, PAI-1-deficient (PAI-1−/−) mice developed severe cardiac fibrosis. However, a marked reduction in cardiac fibrosis was observed in PAI-1−/−/uPA−/− double knockout mice that was associated with reduced inflammation, lower expression levels of TGF-β and proteases associated with tissue remodeling, and diminished Smad2 signaling. Moreover, total ablation of cardiac fibrosis was observed in PAI-1−/− mice that express inactive plasmin (Pm) but normal levels of zymogen Pg (PAI-1−/−/PgS743A/S743A). Our findings indicate that PAI-1 protects mice from hypertension-induced cardiac fibrosis by inhibiting the generation of active Pm.Kamlesh K. GuptaDeborah L. DonahueMayra J. Sandoval-CooperFrancis J. CastellinoVictoria A. PloplisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kamlesh K. Gupta Deborah L. Donahue Mayra J. Sandoval-Cooper Francis J. Castellino Victoria A. Ploplis Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation
description	Abstract Plasminogen activator inhibitor-1 (PAI-1) is known to protect mice against cardiac fibrosis. It has been speculated that PAI-1 may regulate cardiac fibrosis by inactivating urokinase-type plasminogen activator (uPA) and ultimately plasmin (Pm) generation. However, the in vivo role of PAI-1 in inactivating uPA and limiting the generation of Pm during cardiac fibrosis remains to be established. The objective of this study was to determine if the cardioprotective effect of PAI-1 is mediated through its ability to directly regulate urokinase -mediated activation of plasminogen (Pg). An Angiotensin II (AngII)-aldosterone (Ald) infusion mouse model of hypertension was utilised in this study. Four weeks after AngII-Ald infusion, PAI-1-deficient (PAI-1−/−) mice developed severe cardiac fibrosis. However, a marked reduction in cardiac fibrosis was observed in PAI-1−/−/uPA−/− double knockout mice that was associated with reduced inflammation, lower expression levels of TGF-β and proteases associated with tissue remodeling, and diminished Smad2 signaling. Moreover, total ablation of cardiac fibrosis was observed in PAI-1−/− mice that express inactive plasmin (Pm) but normal levels of zymogen Pg (PAI-1−/−/PgS743A/S743A). Our findings indicate that PAI-1 protects mice from hypertension-induced cardiac fibrosis by inhibiting the generation of active Pm.
format	article
author	Kamlesh K. Gupta Deborah L. Donahue Mayra J. Sandoval-Cooper Francis J. Castellino Victoria A. Ploplis
author_facet	Kamlesh K. Gupta Deborah L. Donahue Mayra J. Sandoval-Cooper Francis J. Castellino Victoria A. Ploplis
author_sort	Kamlesh K. Gupta
title	Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation
title_short	Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation
title_full	Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation
title_fullStr	Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation
title_full_unstemmed	Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation
title_sort	plasminogen activator inhibitor-1 protects mice against cardiac fibrosis by inhibiting urokinase-type plasminogen activator-mediated plasminogen activation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/b61808fa7a1343d587e54e6e25fbad0a
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Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation

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