Increased PAI-1 in females compared with males is protective for abdominal aortic aneurysm formation in a rodent model

• Published in: American journal of physiology. Heart and circulatory physiology 2012-04, Vol.302 (7), p.H1378-H1386
• Main Authors: DiMusto, Paul D, Lu, Guanyi, Ghosh, Abhijit, Roelofs, Karen J, Su, Gang, Zhao, Yunge, Lau, Christine L, Sadiq, Omar, McEvoy, Brendan, Laser, Adriana, Diaz, Jose A, Wakefield, Thomas W, Henke, Peter K, Eliason, Jonathan L, Upchurch, Jr, Gilbert R
• Format: Article
• Language: English
• Subjects: Aneurysms; Animals; Aorta, Abdominal - pathology; Aortic Aneurysm, Abdominal - genetics; Aortic Aneurysm, Abdominal - pathology; Aortic Aneurysm, Abdominal - prevention & control; Blotting, Western; Coronary vessels; Densitometry; Female; Fibrinolysin - analysis; Fibrinolysin - metabolism; Gender differences; Genotype & phenotype; Immunohistochemistry; Macrophages - drug effects; Macrophages - metabolism; Male; Matrix Metalloproteinase 2 - biosynthesis; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - genetics; Mice; Mice, Knockout; Pancreatic Elastase - metabolism; Physiology; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - physiology; Real-Time Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Rodents; Sex Characteristics; Urokinase-Type Plasminogen Activator - metabolism; Vascular Biology and Microcirculation
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00620.2011

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.