Elevated Circulating Levels of Inflammatory Cytokines in Patients With Abdominal Aortic Aneurysm

Juvonen, Jukka; Surcel, Heljä‐Marja; Satta, Jari; Teppo, Anna‐Maija; Bloigu, Aini; Syrjälä, Hannu; Airaksinen, Juhani; Leinonen, Maija; Saikku, Pekka; Juvonen, Tatu

doi:10.1161/01.atv.17.11.2843

Cited by 276 publications

(281 citation statements)

References 43 publications

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“…8 -10 IL-6 is increased in atherosclerotic lesions in apoE-KO mice in association with the infiltrating macrophages. 11 In human AAAs, the circulating level of IL-6 has been reported to be elevated 12 and positively correlated with aortic diameter expansion. 13 Consistent with these observations, we showed that ex vivo secretion of IL-6 from the aneurysmal segment of the aorta was increased compared to the aortic arch in Ang II-treated mice and to the aortic segments from the vehicle-treated mice ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

“…8 -10 IL-6 is a marker of vascular inflammation and it has been shown to increase in atherosclerotic lesions in apoE-KO mice in association with the infiltrating macrophages. 11 In human AAAs, the circulating level of IL-6 has been reported to be elevated 12 and positively correlated with aortic diameter expansion. 13 Therefore, the aim of this study was to test the hypothesis that Ang II promotes vascular inflammation that in turn activates the uPA-plasmin-MMP system, thus causing aneurysm in apoE-KO mice.…”

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confidence: 99%

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Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice

Wang¹,

Martin-McNulty²,

Freay

et al. 2001

The American Journal of Pathology

111

125

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Urokinase-type plasminogen activator (uPA) is increased in human abdominal aortic aneurysm (AAA).Chronic infusion of angiotensin II (Ang II) results in AAA in apolipoprotein E-deficient mice. We tested the hypothesis that Ang II infusion results in an elevation of uPA expression contributing to aneurysm formation. Ang II or vehicle was infused by osmotic pumps into apoE-KO mice. All mice treated with Ang II developed a localized expansion of the suprarenal aorta (75% increase in outer diameter), accompanied by an elevation of blood pressure (22 mmHg), compared to the vehicle-treated group. Histological examination of the dilated aortic segment revealed similarities to human AAA including focal elastin fragmentation, macrophage infiltration, and intravascular hemorrhage. Ang II treatment resulted in a 13-fold increase in the expression of uPA mRNA in the AAA segment in contrast to a twofold increase in the atherosclerotic aortic arch. Increased uPA protein was detected in the abdominal aorta as early as 10 days after Ang II infusion before significant aorta expansion. Thus, Ang II infusion results in macrophage infiltration, increased uPA activity, and aneurysm formation in the abdominal aorta of apoE-KO mice. These data are consistent with a causal role for uPA in the pathogenesis of AAA. Abdominal aortic aneurysm (AAA) is a chronic degenerative disease characterized by segmental weakening and dilation of the vascular wall. Recent estimates indicate that the prevalence of AAA is 4 to 9% in adults older than 65 years of age and is known to be associated with atherosclerosis, aging, hypertension, and cigarette smoking. Continued tissue remodeling results in silent expansion of the AAA with an increased risk of spontaneous rupture. Currently the only available treatments for AAAs are surgical resection and replacement or, more recently, insertion of an endovascular stent. The etiology of AAA is unclear. The extracellular matrix plays an essential role in maintaining the integrity of the vascular wall. Elastin and collagen fibers are the major components of this extracellular matrix. Both plasmin and matrix metalloproteinases (MMPs) are capable of degrading extracellular matrix, including collagen, elastin, and fibrin. Urokinase-type plasminogen activator (uPA) hydrolyzes plasminogen to form plasmin, which in turn activates MMPs. The in vivo activity of uPA is also regulated by local concentrations of its major inhibitor, PAI-1. Biochemical studies have demonstrated increased proteolytic activity in the aortic wall of AAA. Schneiderman and colleagues 1 showed that uPA mRNA as well as the tissue-type plasminogen activator (tPA), co-localized with infiltrating macrophages, is significantly increased in human AAA. Increased activities of MMP-2, -3, -9, and -12 in AAA have also been reported. [2][3][4][5] Atherosclerotic aortic lesions from high-cholesterol diet-fed apoE-KO mice show fragmentation of the elastic lamellae and rupture of the media resulting in pseudomicroaneurysm formation. These pathological changes are ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice

Wang¹,

Martin-McNulty²,

Freay

et al. 2001

The American Journal of Pathology

111

125

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“…IFN-␥ can up-regulate MMPs and is increased in AAA, implicating it in AAA pathogenesis (4,21,23,24). To examine the role of IFN-␥ in AAA development, IFN-␥-deficient (IFN-␥ Ϫ/Ϫ ) mice underwent CaCl 2 aneurysm induction.…”

Section: Ifn-␥ Deficiency Prevents Aneurysm Formation and Mmp Up-regumentioning

confidence: 99%

“…IFN-␥, a major inflammatory product of T cells, is a potent activator of macrophage and a cytokine known to regulate MMPs (20). IFN-␥ levels are elevated in AAA (21). Therefore, it is reasonable to speculate that the IFN-␥ may stimulate MMP production from macrophages and SMC, orchestrating progressive destruction of the normal orderly lamellar architecture in AAA.…”

mentioning

confidence: 99%

Key Roles of CD4+ T Cells and IFN-γ in the Development of Abdominal Aortic Aneurysms in a Murine Model

Xiong

Zhao

Prall

et al. 2004

The Journal of Immunology

188

187

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Abdominal aortic aneurysm (AAA) is one of a number of diseases associated with a prominent inflammatory cell infiltrate and local destruction of structural matrix macromolecules. This inflammatory infiltrate is predominately composed of T lymphocytes and macrophages. Delineating specific contribution of these inflammatory cells and their cytokines in AAA formation is the key to understanding AAA and other chronic inflammatory disease processes. Our previous studies have demonstrated that macrophages are the major source of matrix metalloproteinase-9, which is required for aneurysmal degeneration in the murine AAA model. However, the role of CD4+ T cells, the most abundant infiltrates in aneurysmal aortic tissue, is uncertain. In the present study, we found that in the absence of CD4+ T cells, mice are resistant to aneurysm induction. Previous studies have shown that IFN-γ levels are increased in AAA. IFN-γ is a main product of T cells. Intraperitoneal IFN-γ was able to partially reconstitute aneurysms in CD4−/− mice. Furthermore, mice with a targeted deletion of IFN-γ have attenuation of MMP expression and inhibition of aneurysm development. Aneurysms in IFN-γ−/− mice can be reconstituted by reinfusion of competent splenocytes from the corresponding wild-type mice. This study demonstrates the pivotal role that T cells and the T cell cytokine, IFN-γ, play in orchestrating matrix remodeling in AAA. This study has important implications for other degenerative diseases associated with matrix destruction.

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“…Interleukin-1 (IL-1) is a key cytokine in the inflammatory cascade [84] and is a central factor and powerful modulator of AAA genesis and progression [85][86][87]. Production of IL1β was significantly higher in aneurysmal tissues than control aortic tissue from cadaveric donors [87].…”

Section: Interleukin-1mentioning

confidence: 99%

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

Fraga‐Silva

Trachet²,

Stergiopulos³

2015

CPD

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Abdominal aortic aneurysm (AAA) is a local expansion of the abdominal aorta wall caused by a complex multifactorial maladaptive vascular remodeling. Despite recent advances in the management of cardiovascular diseases, there currently is no established drug therapy for AAA. Since the probability of death from a ruptured AAA still remains high, preventive elective repair of AAAs larger than 5.5 cm in luminal diameter is considered the best treatment option. However, perioperative complications are problematic as elective AAA repair comes with numerous intrinsic risks. Impelled by the need of improving AAA therapy, significant efforts have been made to identify pharmacological tools that would slow down AAA enlargement and lower the risk of rupture, thereby reducing the necessity of surgical intervention. In this review, we discuss recent findings addressing molecular targets that could potentially treat AAA, particularly addressing: statins, classical renin angiotensin system (RAS) blockers, the protective arm of RAS, renin inhibitors, tetracyclines, interleukin-1β inhibition, anti-angiogenic agents and urocortins.

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Elevated Circulating Levels of Inflammatory Cytokines in Patients With Abdominal Aortic Aneurysm

Cited by 276 publications

References 43 publications

Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice

Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice

Key Roles of CD4+ T Cells and IFN-γ in the Development of Abdominal Aortic Aneurysms in a Murine Model

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

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