Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of matrix metalloproteinases (MMPs) in abdominal aortic aneurysm (AAA) pathogenesis is well described. However, a clear role for the MMPs in disease prediction has not been established. The aim of this study was to determine if circulating levels of MMPs correlated with AAA diameter and with MMP concentrations within the aneurysm wall. Preoperative plasma samples and intraoperative infrarenal AAA sac biopsies were taken in a standard fashion from 31 patients undergoing elective repair.The concentrations of MMP-1, MMP-2, MMP-3, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and TIMP-2 were quantified in plasma and aneurysm wall homogenates using enzyme-linked immunosorbent assay. Comparison used the Spearman correlation. There were no correlations between the paired plasma and aneurysm wall concentrations for any MMP or TIMP. Correlation between MMP-9 levels in the aneurysm wall and aneurysm diameter was negative (r = -.42, p = .019). Other correlations between plasma and tissue levels with aneurysm diameter were nonsignificant.
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PMID:Plasma matrix metalloproteinase levels do not predict tissue levels in abdominal aortic aneurysms suitable for elective repair. 1923 64

Inflammation and oxidative stress are pathogenic mediators of many diseases, but molecules that could be therapeutic targets remain elusive. Inflammation and matrix degradation in the vasculature are crucial for abdominal aortic aneurysm (AAA) formation. Cyclophilin A (CypA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMCs), is secreted in response to reactive oxygen species (ROS) and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe-/- mice, we show that Apoe-/-Ppia-/- mice are completely protected from AngII-induced AAA formation, in contrast to Apoe-/-Ppia+/+ mice. Apoe-/-Ppia-/- mice show decreased inflammatory cytokine expression, elastic lamina degradation and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia+/+ mice. Mechanistic studies showed that VSMC-derived intracellular and extracellular CypA are required for ROS generation and matrix metalloproteinase-2 activation. These data define a previously undescribed role for CypA in AAA formation and suggest CypA as a new target for treating cardiovascular disease.
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PMID:Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms. 1943 Apr 89

Abdominal aortic aneurysm (AAA) is a very significant health problem in the United States. Current therapeutic options are surgery or endovascular stenting. Medical treatment is not very effective and there is no medical therapy that can effect the regression of AAA. Surgical or endovascular intervention for many older patients will be unnecessary if medications could prevent or reduce the progression rate of small AAA by 50%. Basic research has helped to determine the molecular basis of pathogenesis in AAA. Mediators of aortic damage include angiotensin II, leukotriene-LT4, prostaglandin- PGE2, interleukins, tumor necrosis factor, tissue plasminogen activator, c-Jun N-terminal Kinase, NF-kappaB, Rho kinases, osteoprotegerin and chymases. They work in concert to activate matrix metalloproteinase, serine proteases and cysteine proteases. The result is degradation of aortic wall proteins, extracellular matrix and apoptosis of vascular smooth muscle cells. An enhanced understanding of the pathogenetic pathways has led to significant research and development of new molecules, which can inhibit these pathways and delay the expansion of AAA. We discuss newly patented agents that may have a beneficial role in preventing the progression of AAA.
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PMID:Molecular targets and abdominal aortic aneurysms. 1951 57

To summarize the present evidence for an association between matrix metalloproteinase-9 (MMP-9) and abdominal aortic aneurysm (AAA) presence, we performed a meta-analysis of case-control studies that compared circulating MMP-9 concentrations between patients with AAA and subjects without AAA. MEDLINE database was searched to identify all case-control studies. For each study, data regarding serum or plasma MMP-9 concentrations in both the AAA and control groups were used to generate standardized mean differences (SMDs) and 95% confidence intervals (CIs). Study-specific estimates were combined using inverse variance-weighted average of logarithmic SMDs in both fixed- and random-effects models. Our search identified eight eligible studies including 580 patients with AAA and 258 subjects without AAA. Pooled analysis demonstrated significantly higher circulating MMP-9 concentrations in the AAA group than those in the control group in random-effect models (SMD, 0.70; 95% CI, 0.23-1.17; P=0.004). There was significant study heterogeneity of results (P<0.00001) but no evidence of significant publication bias (P=0.1376). We found that, based on a systematic review and meta-analysis, circulating MMP-9 concentrations are higher in patients with AAA than those in subjects without AAA. Higher circulating MMP-9 concentrations are associated with AAA presence.
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PMID:Circulating matrix metalloproteinase-9 concentrations and abdominal aortic aneurysm presence: a meta-analysis. 1952 92

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 chronic infiltrate is predominately composed of macrophages and T lymphocytes. Activated macrophages produce a variety of cytokines, including TNF-alpha. Elevated levels of TNF-alpha were observed in patients with AAA, suggesting that TNF-alpha may play a role in the pathogenic mechanisms of AAA. In the present study, we investigated the role of TNF-alpha in AAA formation. By studying a murine aneurysm model, we found that both mRNA and protein levels of TNF-alpha were increased in aneurysm tissue compared with normal aortic tissues. Therefore, we tested the response of mice lacking expression of TNF-alpha. These mice were resistant to aneurysm formation. Our results show that TNF-alpha deficiency attenuates matrix metalloproteinase (MMP) 2 and MMP-9 expression and macrophage infiltration into the aortic tissue. These data suggest that TNF-alpha plays a central role in regulating matrix remodeling and inflammation in the aortic wall leading to AAA. In addition, we investigated the pharmacological inhibition of AAA. A Food and Drug Administration-approved TNF-alpha antagonist, infliximab, inhibited aneurysm growth. Our data also show that infliximab treatment attenuated elastic fiber disruption, macrophage infiltration, and MMP-2 and MMP-9 expression in aortic tissue. This study confirms that a strategy of TNF-alpha antagonism may be an important therapeutic strategy for treating AAA.
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PMID:Blocking TNF-alpha attenuates aneurysm formation in a murine model. 1962 Feb 91

We previously reported that Brown Norway Katholiek rats, which feature a deficiency of plasma kininogens, develop severe abdominal aortic aneurysm. Increased activity of matrix metalloproteinases (MMPs) in the aortic wall, leading to degradation of extracellular matrix components, is considered to play a crucial role in aneurysm formation. Using an in vitro model of vascular smooth muscle cells (VSMCs), cultured from the rat aorta, we investigated whether the cleaved form of high molecular weight kininogen, designated HKa, affects the expression of MMP-9 and MMP-2 and their tissue inhibitors (TIMPs). Treatment of VSMCs with HKa reduced in a concentration-dependent manner IL-1alpha-induced release of MMP-9 and MMP-2, associated with decreased MMP enzymatic activity levels in conditioned media, as demonstrated by gelatin zymography and fluorescein-labeled gelatin substrate assay, respectively. Real-time PCR revealed that HKa reduced corresponding MMP-9 mRNA levels. Further investigations showed that this effect did not result from a modified rate of MMP-9 mRNA degradation. TIMP-1 mRNA levels, already increased as a result of cytokine-stimulation, were significantly enhanced by HKa. Furthermore, we found elevated basal mRNA expression levels of MMP-2 and TIMP-2 in VSMCs derived from kininogen-deficient Brown Norway Katholiek rats. These results demonstrate for the first time that HKa affects the regulation of MMPs in VSMCs.
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PMID:Cleaved high molecular weight kininogen, a novel factor in the regulation of matrix metalloproteinases in vascular smooth muscle cells. 1968 38

Abdominal aortic aneurysm is a multifactorial disease with genetic risk factors and an immunologic component. Immune cells, including macrophages, neutrophils, mast cells, B- and T- lymphocytes, along with vascular smooth muscle cells and adventitial fibroblasts, produce cytokines and enzymes, promoting an inflammatory reaction, extracellular matrix degradation, and neovascularization. Among the different enzymes secreted by immune and stromal cells, matrix metalloproteinase (MMP)-2, MMP-9, MMP-12, cathepsins, and neutrophil elastase cause medial degeneration. Chymase causes smooth muscle cell apoptosis, and MMP-3, MMP-8, and MMP-13 cause adventitial collagen degradation, promoting abdominal aortic aneurysm rupture. At the same time chemokines (interleukin 8, macrophage inflammatory protein 1 alpha, monocyte chemotactic protein-1) cause recruitment and proliferation of inflammatory cells, whereas cytokines (vascular endothelial growth factor and transforming growth factor-beta) promote neoangiogenesis.
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PMID:Immune cells and molecular mediators in the pathogenesis of the abdominal aortic aneurysm. 1969 Apr 70

Statins may reduce abdominal aortic aneurysm (AAA) progression. We sought to measure how atorvastatin (AT) treatment might modulate matrix metalloproteinase (MMP) expression and/or activity in human AAA. Tissue from human AAAs at surgical repair was obtained from patients who were either not on statins (NST, n = 19) or treated with AT (n = 19). Immunoblots measured expression and zymography measured activity. Expression of most proteins was greater in the central compared with distal AAA region. Matrix metalloproteinase 1, MMP2, MMP3, MMP9, Tissue Inhibitor of Metalloproteinase (TIMP2), TIMP3, TIMP4, or total Sma Mothers Against Decapentaplegia (SMAD2) expression did not differ with treatment. There was a trend toward reduced MMP8 and TIMP1 expression and MMP2 zymographic activity in the AT-treatment group. In contrast, AT-treated samples had significantly reduced MMP13 (P = .02), latent-transforming growth factor (TGF)-beta (P = .02), and phospho-SMAD2 (P = .029) expression than NST-treated samples. We conclude that the AT-mediated decrease in MMP expression and activity reduces TGF-beta signaling in the central region of human AAAs.
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PMID:Atorvastatin modulates matrix metalloproteinase expression, activity, and signaling in abdominal aortic aneurysms. 2003 37

To investigate the effects of a tissue inhibitor of the matrix metalloproteinase-2 (TIMP-2) gene on the extracellular matrix of the abdominal aorta, models of rat abdominal aortic aneurysm were utilized and a solution of AdTIMP-2 was perfused into the abdominal aorta. The models of rat abdominal aortic aneurysm were constructed with intraluminal perfusion of the abdominal aorta with porcine pancreatic elastase, and an adenovirus solution carrying the TIMP-2 gene was transferred into the aorta by local perfusion. After 14 days, aortic wall elastin and collagen concentrations were measured with an image analysis system and fixed aortic tissues were examined by light microscopy for inflammation. No abdominal aortic aneurysms developed in TIMP-2 gene-transferred rat models, representing a marked decreased from control rats (p < 0.01). The elastic fibers and collagenous fibers were preserved with greater integrity in the AdTIMP-2 group than in the control group and inflammatory cells were seen in adventitial areas. The TIMP-2 gene mediated by adenovirus can renew the balance of degradation of the extracellular matrix caused by elastase and inhibit the formation of an abdominal aortic aneurysm. This finding provides a new strategy for treatment of abdominal aortic aneurysms.
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PMID:Overexpression of TIMP-2 mediated by recombinant adenovirus in rat abdominal aorta inhibits extracellular matrix degradation. 2010 29

Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expression of transforming growth factor (TGF)-beta and matrix metalloproteinase (MMP)-9 precursors, and chymase can convert precursors of TGF-beta and MMP-9 to their active forms. In cultured fibroblasts, significant increases in cell growth and TGF-beta levels were observed after chymase injection; these increases were inhibited by a chymase inhibitor, but not by an angiotensin II-receptor blocker. In apolipoprotein E-deficient mice, abdominal aortic aneurysm (AAA) development depends on an increase in MMP-9 activities induced by angiotensin II infusion, but the inhibition of MMP-9 activation by a chymase inhibitor resulted in attenuation of the angiotensin II-induced AAA development. The upregulation of MMP-9 and TGF-beta levels is involved in damage to various organs, but these gene expressions are not completely induced by angiotensin II alone. Therefore, chymase inhibition may be useful for attenuating MMP-9 and TGF-beta levels, in addition to reducing angiotensin II formation, and this function may provide powerful organ protection. In this review, we propose the possible use of chymase inhibitors as agents to prevent organ damage.
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PMID:New approaches to blockade of the renin-angiotensin-aldosterone system: chymase as an important target to prevent organ damage. 2067 58


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