Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice

Hs, Qian; Jm, Gu; P, Liu; Kauser, Katalin; Halks-Miller, Meredith; Vergona, Ronald; Me, Sullivan; Wp, Dole; Gg, Deng

doi:10.1038/sj.gt.3303069

Cited by 42 publications

(37 citation statements)

References 44 publications

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“…These larger aneurysms were associated with increases in pro and active MMP-2 and increased macrophage influx, both factors known to be important in AAA formation. While previous studies have demonstrated that local overexpression of PAI-1 using molecular biology techniques in rodent models prevents aneurysm formation (1,33), and that patients with higher PAI-1 levels are protected from AAA formation, to our knowledge this is the first report of differences in PAI-1 between genders during the process of AAA formation in a rodent model. This difference in PAI-1 between males and females may indeed partially explain the gender difference seen in the incidence of AAAs in humans.…”

Section: Discussionmentioning

confidence: 81%

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

DiMusto

Ghosh

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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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.

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Section: Discussionmentioning

confidence: 81%

“…Additionally, nearly 40-fold higher levels of plasmin have been detected in the aortic wall of patients with AAAs compared with normal controls (19). Finally, localized overexpression of PAI-1 has been shown to prevent AAA development and rupture in animal models (1,33).…”

mentioning

confidence: 99%

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

DiMusto

Ghosh

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…26 Indeed, mice deficient in plasminogen and urokinase and those overexpressing plasminogen activator inhibitor-1 (PAI-1) are protected from experimental AAA development. 26,27,29 We demonstrated that inhibition of plasmin generation from plasminogen by TA attenuates AAA formation in pCPB Ϫ/Ϫ mice, indicating that unregulated plasmin generation in the absence of CPB within the infused aortic segment promotes inflammation and aneurysmal degeneration of the aorta (Figure 4). TA completely abolished AAA rupture in pCPB Ϫ/Ϫ animals after PPE, 10 U/mL, infusion.…”

Section: C5mentioning

confidence: 99%

Enhanced Abdominal Aortic Aneurysm Formation in Thrombin-Activatable Procarboxypeptidase B–Deficient Mice

Schultz

Tedesco

Sho

et al. 2010

ATVB

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Objective-To determine whether procarboxypeptidase B (pCPB)Ϫ/Ϫ mice are susceptible to accelerated abdominal aortic aneurysm (AAA) development secondary to unregulated OPN-mediated mural inflammation in the absence of CPB inhibition. Methods and Results-Thrombin/thrombomodulin cleaves thrombin-activatable pCPB or thrombin-activatable fibrinolysis inhibitor, activating CPB, which inhibits the generation of plasmin and inactivates proinflammatory mediators (complement C5a and thrombin-cleaved osteopontin [OPN] Key Words: thrombosis Ⅲ abdominal aortic aneurysm Ⅲ carboxypeptidase Ⅲ osteopontin Ⅲ plasmin A bdominal aortic aneurysm (AAA) is a common and potentially lethal disease, found in approximately 6% to 8% of men older than 60 years. AAA rupture is the most serious consequence of the disease and accounts for approximately 15 000 deaths in the United States annually. 1,2 The pathogenesis of AAA disease is complex, involving chronic transmural inflammation, characterized by macrophage and lymphocyte infiltration and proteolytic degradation of medial elastin and interstitial collagens by matrix metalloproteinases (MMPs). Structural degradation of the aortic wall in combination with hemodynamic stress results in tissue failure and aneurysmal dilatation. 3 Osteopontin (OPN) is a multifunctional protein that is both a component of the extracellular matrix (ECM) in mineralized tissues and a circulating proinflammatory cytokine. 4 OPN is a prominent component of human atherosclerotic tissues and has recently been demonstrated to play a key role in AAA pathogenesis. 5 Compared with apolipoprotein E (ApoE) Ϫ/Ϫ mice, ApoE Ϫ/Ϫ OPN Ϫ/Ϫ double-knockout mice are protected from angiotensin II-induced accelerated atherosclerosis and AAA formation. 6 Structurally, OPN contains an RGD site (159 -161) that mediates binding to a number of integrins, including ␣v␤1, ␣v␤3, ␣v␤5, and ␣5␤1. Thrombin cleavage of OPN exposes a hitherto cryptic C-terminus ( 162 SVVYGLR 168 ) that mediates the binding of thrombincleaved OPN (OPN-R) to a new subset of integrins, consisting of ␣4␤1 and ␣9␤1. 7-9 OPN-R demonstrates enhanced cell binding and cell migration compared with intact OPN in vitro, 10,11 suggesting that thrombin cleavage of OPN may augment its proinflammatory properties.When thrombin binds to thrombomodulin on the endothelial cell surface, it undergoes a remarkable change in its substrate recognition, switching from procoagulant factors, such as fibrinogen, to protein C and functionally inhibiting progressive thrombosis. 12 In addition to inhibiting coagulation via the activation of protein C, the thrombinthrombomodulin complex also influences fibrinolysis by activating a second physiological substrate, the plasma carboxypeptidase, thrombin-activatable procarboxypeptidase B (pCPB), or thrombin-activatable fibrinolysis inhibitor. 13,14

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“…Using genetargeted mice, studies have shown that the Plg system regulates leukocyte recruitment in inflammation (11)(12)(13)(14) as well as in inflammation-associated CVD, including AAA (15)(16)(17). Mice deficient in uPA (18,19) or overexpressing PAI-1 (20) are protected from aneurysm formation, suggesting that Plg system and its regulated macrophage infiltration are essential to aneurysm development. Plg is able to directly bind to the ECM and upon its conversion to plasmin can degrade multiple ECM proteins (21).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice

Gong¹,

Hart²,

Shchurin³

et al. 2008

J. Clin. Invest.

294

318

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Inflammation plays a critical role in the development of cardiovascular diseases. Infiltration of leukocytes to sites of injury requires their exit from the blood and migration across basement membrane; this process has been postulated to require remodeling of the ECM. Plasminogen (Plg) is a protease that binds to the ECM and, upon conversion to plasmin, degrades multiple ECM proteins. In addition, plasmin directly activates MMPs. Here, we used Plg -/-mice to investigate the role of Plg in inflammatory leukocyte migration. After induction of peritonitis by thioglycollate injection, we found that Plg -/-mice displayed diminished macrophage trans-ECM migration and decreased MMP-9 activation. Furthermore, injection of the active form of MMP-9 in Plg -/-mice rescued macrophage migration in this model. We used periaortic application of CaCl 2 to induce abdominal aortic aneurysm (AAA) and found that Plg -/-mice displayed reduced macrophage infiltration and were protected from aneurysm formation. Administration of active MMP-9 to Plg -/-mice promoted macrophage infiltration and the development of AAA. These data suggest that Plg regulates macrophage migration in inflammation via activation of MMP-9, which, in turn, regulates the ability of the cells to migrate across ECM. Thus, targeting the Plg/MMP-9 pathway may be an attractive approach to regulate inflammatory responses and AAA development.

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Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice

Cited by 42 publications

References 44 publications

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

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

Enhanced Abdominal Aortic Aneurysm Formation in Thrombin-Activatable Procarboxypeptidase B–Deficient Mice

Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice

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