Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation.
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.
W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, USA.
Kamlesh K
KK
Gupta
W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, USA.
Deborah L
0000-0001-8137-0692
DL
Donahue
W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, USA.
Mayra J
MJ
Sandoval-Cooper
W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, USA.|Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
Francis J
FJ
Castellino
W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, USA. vploplis@nd.edu.|Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. vploplis@nd.edu.
Victoria A
VA
Ploplis
D000818:Animals; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000378:metabolism*; D005355:Fibrosis; D015870:Gene Expression; D006331:Heart Diseases / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D006973:Hypertension / Q000150:complications; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010958:Plasminogen / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D017395:Plasminogen Activator Inhibitor 1; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D010958:Plasminogen; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator