Increased PAI-1 in females compared with males is protective for abdominal aortic aneurysm formation in a rodent model.
The serine proteases, along with their inhibitor plasmin activator inhibitor-1 (PAI-1), have been shown to play a role in abdominal aortic aneurysm (AAA) formation. The aim of this study is to determine if PAI-1 may be a protective factor for AAA formation and partially responsible for the gender difference observed in AAAs. Male and female wild-type (WT) C57BL/6 and PAI-1(-/-) mice 8-12 wk of age underwent aortic perfusion with porcine pancreatic elastase. Animals were harvested 14 days following perfusion and analyzed for phenotype, PAI-1 protein levels, and matrix metalloproteinase (MMP)-9 and -2 activity. WT males had an average increase in aortic diameter of 80%, whereas females only increased 32% (P < 0.001). PAI-1(-/-) males increased 204% and females 161%, significantly more than their WT counterparts (P < 0.001). Western blot revealed 61% higher PAI-1 protein levels in the WT females compared with the WT males (P = 0.01). Zymography revealed higher levels of pro-MMP-2 and active MMP-2 in the PAI-1(-/-) males and females compared with their WT counterparts. PAI-1(-/-) females had significantly higher serum plasmin levels compared with WT females (P = 0.003). In conclusion, WT female mice are protected from aneurysm formation and have higher levels of PAI-1 compared with males during experimental aneurysm formation. Additionally, both male and female PAI-1(-/-) animals develop significantly larger aneurysms than WT animals, correlating with higher pro- and active MMP-2 levels. These findings suggest that PAI-1 is protective for aneurysm formation in the elastase model of AAA and plays a role in the gender differences seen in AAA formation.
Jobst Vascular Research Laboratory, Department of Surgery, University of Michigan, Ann Arbor, USA.
Paul D
PD
DiMusto
Guanyi
G
Lu
Abhijit
A
Ghosh
Karen J
KJ
Roelofs
Gang
G
Su
Yunge
Y
Zhao
Christine L
CL
Lau
Omar
O
Sadiq
Brendan
B
McEvoy
Adriana
A
Laser
Jose A
JA
Diaz
Thomas W
TW
Wakefield
Peter K
PK
Henke
Jonathan L
JL
Eliason
Gilbert R
GR
Upchurch
D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D003720:Densitometry; D005260:Female; D005341:Fibrinolysin / Q000032:analysis / Q000378:metabolism; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010196:Pancreatic Elastase / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012727:Sex Characteristics; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D010196:Pancreatic Elastase; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9