Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-00418-y
Keywords
-
Categories
Funding
- AHA Midwest [12GRNT12070118]
- NIH/NHLBI [RO1 HL013423]
Ask authors/readers for more resources
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-beta 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 (PAI1(-/-)/Pg(S743A/S743A)). Our findings indicate that PAI-1 protects mice from hypertension-induced cardiac fibrosis by inhibiting the generation of active Pm.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available