Inflammation and Matrix Metalloproteinases in the Enlarging Abdominal Aortic Aneurysm

Freestone, Tim; Turner, Robert; Coady, A.; Higman, D. J.; Greenhalgh, Roger M.; Powell, Janet T.

doi:10.1161/01.atv.15.8.1145

Cited by 609 publications

(509 citation statements)

References 18 publications

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“…A growing number of reports indicate that proteolytic breakdown of extracellular matrix by MMPs contribute to VSMCs migration 31. Moreover, mice deficient in MMP‐2 are actually resistant to aneurysm formation, indicating that MMP‐2 is a causative factor in the pathogenesis of AAA 17, 32.…”

Section: Discussionmentioning

confidence: 99%

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

Peng

Zhang

Liu

et al. 2018

JAHA

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BackgroundHydrogen peroxide (H2O2) is a critical molecular signal in the development of abdominal aortic aneurysm (AAA) formation. Vascular peroxidase 1 (VPO1) catalyzes the production of hypochlorous acid (HOCl) from H2O2 and significantly enhances oxidative stress. The switch from a contractile phenotype to a synthetic one in vascular smooth muscle cells (VSMCs) is driven by reactive oxygen species and is recognized as an early and important event in AAA formation. This study aims to determine if VPO1 plays a critical role in the development of AAA by regulating VSMC phenotypic switch.Methods and Results VPO1 is upregulated in human and elastase‐induced mouse aneurysmal tissues compared with healthy control tissues. Additionally, KLF4, a nuclear transcriptional factor, is upregulated in aneurysmatic tissues along with a concomitant downregulation of differentiated smooth muscle cell markers and an increase of synthetic phenotypic markers, indicating VSMC phenotypic switch in these diseased tissues. In cultured VSMCs from rat abdominal aorta, H2O2 treatment significantly increases VPO1 expression and HOCl levels as well as VSMC phenotypic switch. In support of these findings, depletion of VPO1 significantly attenuates the effects of H2O2 and HOCl treatment. Furthermore, HOCl treatment promotes VSMC phenotypic switch and ERK1/2 phosphorylation. Pretreatment with U0126 (a specific inhibitor of ERK1/2) significantly attenuates HOCl‐induced VSMC phenotypic switch.ConclusionsOur results demonstrate that VPO1 modulates VSMC phenotypic switch through the H2O2/VPO1/HOCl/ERK1/2 signaling pathway and plays a key role in the development of AAA. Our findings also implicate VPO1 as a novel signaling node that mediates VSMC phenotypic switch and plays a key role in the development of AAA.Clinical Trial Registration URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1800016922.

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Section: Discussionmentioning

confidence: 99%

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

Peng

Zhang

Liu

et al. 2018

JAHA

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“…The prominent inflammatory infiltrate has been implicated in the pathogenesis of AAA (16,18). While studies of human tissues demonstrate the association between matrix destruction and inflammatory cells, animal data is even more compelling in demonstrating a causal role for local inflammation in AAA pathogenesis (8,25,26).…”

Section: Discussionmentioning

confidence: 99%

“…It is primarily produced by aneurysm-infiltrating macrophages at the sites of tissue damage and its expression appears to correlate with increasing aneurysm diameter (14,15). MMP-2 expression is elevated in human AAA (9,16,17). It is primarily produced by resident mesenchymal cells in AAA (9).…”

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

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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“…1,2,4,17 Many pro-MMPs are activated by plasmin which, in turn, is activated by uPA. uPA expression was increased 13-fold in the aneurysmal segment of Ang II-treated apoE-KO mice compared to vehicletreated controls.…”

Section: Discussionmentioning

confidence: 99%

“…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 not observed in mice deficient in both apoE and uPA, 6 suggesting that uPA may play a key role in matrix destruction and aneurysm formation.…”

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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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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Inflammation and Matrix Metalloproteinases in the Enlarging Abdominal Aortic Aneurysm

Cited by 609 publications

References 18 publications

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

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

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

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