The Controversial Role of the Urokinase System in Abdominal Aortic Aneurysm Formation and Rupture

Rein, Chantelle M.; Cardenas, Jessica C.; Church, Frank C.

doi:10.1161/atvbaha.111.237123

Cited by 7 publications

(4 citation statements)

References 13 publications

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“…420 These studies have indicated that u-PA has potentially paradoxical roles in the development of AAD vs aneurysm rupture. 421 PAI-1 in AAD-PAI-1 expression is increased in the aortic media of TAA tissues 413 but is decreased in AAA tissues. 422 Interestingly, the deficiency of Pai-1 in mice resulted in increased MMP-2 levels and promoted aneurysm formation.…”

Section: Plasmin Plasminogen and Plasminogen Activators And Thrombosismentioning

confidence: 98%

Molecular pathogenesis of genetic and sporadic aortic aneurysms and dissections

Shen

LeMaire

2017

Current Problems in Surgery

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the descending thoracic aorta; and 10% involve the thoracoabdominal aorta. 3 Thoracic aortic dissection (TAD) is estimated to occur at a rate of 3 cases per 100,000 individuals per year. [4][5][6][7] The prevalence of infrarenal abdominal aortic aneurysms (AAA) is estimated to be between 2.2% and 5% in men older than 55 years of age. 3,8,9 AAD are highly lethal conditions that often necessitate surgical treatment. Operative treatment generally involves replacing the diseased segment with a prosthetic graft by using an open surgical, endovascular, or hybrid approach. Despite significant improvements in the surgical treatment of AAD, they cause more than 10,000 deaths in the United States each year. Although AAD are a leading cause of death in people 55 years of age or older, 10,11 AAD are also a significant cause of morbidity and mortality in children and young adults. 12 Recent reports indicate that the mortality rate of acute TAAD is 16%. 2 AAD are particularly lethal when they involve the ascending aorta. The current incidence of in-hospital death is 24% for patients presenting with acute ascending aortic dissection (ie, DeBakey type I or II dissection and Stanford type A dissection). 13 Normal structure and function of the aorta Histology of the aortic wallThe aortic wall is composed of 3 layers (Fig 3A): a thin inner layer (the intima), a thick medial layer (the media), and a thin outer layer (the tunica adventitia). The intima is lined with a monolayer of endothelial cells that not only separates the aortic wall from circulating blood but also regulates vascular functions. 30

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Section: Plasmin Plasminogen and Plasminogen Activators And Thrombosismentioning

confidence: 98%

Molecular pathogenesis of genetic and sporadic aortic aneurysms and dissections

Shen

LeMaire

2017

Current Problems in Surgery

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“…In watchful waiting patients, we found a borderline significant association between uPA and aneurysm volume. In several murine models, uPA was investigated as a possible mediator of proteolysis and inflammation in AAA 38 and uPA plays a pivotal role in extracellular matrix degradation. 39 The exact mechanisms, however, to stimulate AAA are not yet defined.…”

Section: Discussionmentioning

confidence: 99%

Circulating biomarkers of cardiovascular disease are related to aneurysm volume in abdominal aortic aneurysm

Bouwens,

Vanmaele,

Hoeks

et al. 2023

Vasc Med

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Background: Surveillance programs in abdominal aortic aneurysms (AAA) are mainly based on imaging and leave room for improvement to timely identify patients at risk for AAA growth. Many biomarkers are dysregulated in patients with AAA, which fuels interest in biomarkers as indicators of disease progression. We examined associations of 92 cardiovascular disease (CVD)-related circulating biomarkers with AAA and sac volume. Methods: In a cross-sectional analysis, we separately investigated (1) 110 watchful waiting (WW) patients (undergoing periodic surveillance imaging without planned intervention) and (2) 203 patients after endovascular aneurysm repair (EVAR). The Cardiovascular Panel III (Olink Proteomics AB, Sweden) was used to measure 92 CVD-related circulating biomarkers. We used cluster analyses to investigate protein-based subphenotypes, and linear regression to examine associations of biomarkers with AAA and sac volume on CT scans. Results: Cluster analyses revealed two biomarker-based subgroups in both WW and EVAR patients, with higher levels of 76 and 74 proteins, respectively, in one subgroup versus the other. In WW patients, uPA showed a borderline significant association with AAA volume. Adjusting for clinical characteristics, there was a difference of −0.092 (−0.148, −0.036) loge mL in AAA volume per SD uPA. In EVAR patients, after multivariable adjustment, four biomarkers remained significantly associated with sac volume. The mean effects on sac volume per SD difference were: LDLR: −0.128 (−0.212, −0.044), TFPI: 0.139 (0.049, 0.229), TIMP4: 0.110 (0.023, 0.197), IGFBP-2: 0.103 (0.012, 0.194). Conclusion: LDLR, TFPI, TIMP4, and IGFBP-2 were independently associated with sac volume after EVAR. Subgroups of patients with high levels of the majority of CVD-related biomarkers emphasize the intertwined relationship between AAA and CVD. ClinicalTrials.gov Identifier: NCT03703947.

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“…Previous reports have shown that the enzymes of the fibrinolytic system are also involved in AAA progression (38,39) and local overexpression of PAI-1 in the mouse was accordingly reported to prevent the development of the disease (40). The role of the plasminergic system remains nevertheless incompletely understood (41) and the study of PN-1 in this context could provide new insights into the understanding of how proteases and their counter-regulators participate in the evolution of AAA.…”

Section: Pn-1 and Aneurysmsmentioning

confidence: 99%

Protease Nexin-1 in the Cardiovascular System: Wherefore Art Thou?

Madjene

Boutigny

Bouton

et al. 2021

Front. Cardiovasc. Med.

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The balance between proteases and protease inhibitors plays a critical role in tissue remodeling during cardiovascular diseases. Different serine protease inhibitors termed serpins, which are expressed in the cardiovascular system, can exert a fine-tuned regulation of protease activities. Among them, protease nexin-1 (PN-1, encoded by SERPINE2) is a very powerful thrombin inhibitor and can also inactivate plasminogen activators and plasmin. Studies have shown that this serpin is expressed by all cell subpopulations in the vascular wall and by circulating cells but is barely detectable in plasma in the free form. PN-1 present in platelet granules and released upon activation has been shown to present strong antithrombotic and antifibrinolytic properties. PN-1 has a broad spectrum of action related to both hemostatic and blood vessel wall protease activities. Different studies showed that PN-1 is not only an important protector of vascular cells against protease activities but also a significant actor in the clearance of the complexes it forms with its targets. In this context, PN-1 overexpression has been observed in the pathophysiology of thoracic aortic aneurysms (TAA) and during the development of atherosclerosis in humans. Similarly, in the heart, PN-1 has been shown to be overexpressed in a mouse model of heart failure and to be involved in cardiac fibrosis. Overall, PN-1 appears to serve as a “hand brake” for protease activities during cardiovascular remodeling. This review will thus highlight the role of PN-1 in the cardiovascular system and deliver a comprehensive assessment of its position among serpins.

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The Controversial Role of the Urokinase System in Abdominal Aortic Aneurysm Formation and Rupture

Cited by 7 publications

References 13 publications

Molecular pathogenesis of genetic and sporadic aortic aneurysms and dissections

Molecular pathogenesis of genetic and sporadic aortic aneurysms and dissections

Circulating biomarkers of cardiovascular disease are related to aneurysm volume in abdominal aortic aneurysm

Protease Nexin-1 in the Cardiovascular System: Wherefore Art Thou?

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