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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abdominal aortic aneurysm (AAA) is a common vascular disease with, as of yet, unclear mechanism. Increased elastase activity and elastin degradation in the aorta are consistent findings in human AAA. Also, elastase perfusion of the aorta promotes aortic dilation in animal models of AAA. Although elastase-induced degradation of extracellular matrix proteins and the ensuing inflammation of the aortic wall have been implicated as possible causes of the aortic dilation in AAA, little is known regarding the effects of elastase on the mechanisms of aortic smooth muscle contraction. The purpose of this study was to test the hypothesis that elastase promotes aortic dilation by inhibiting the Ca2+ mobilization mechanisms of smooth muscle contraction. Isometric contraction and 45Ca2+ influx were measured in aortic strips isolated from male Sprague-Dawley rats non-treated or treated with elastase. Initial experiments suggested that elastase alone caused matrix degradation. To avoid potential degradation of the extracellular matrix proteins by elastase, the same experiments were repeated in the presence of saturating concentrations of elastin (10 mg/ml). In normal Krebs (2.5 mM Ca2+), phenylephrine (Phe, 10(-5) M) caused contraction of the aortic strips that was significantly inhibited by elastase. The elastase-induced inhibition of Phe contraction was concentration- and time-dependent. At 5 U/ml elastase, the inhibition of Phe contraction was rapid in onset (2.4 +/- 0.3 minutes) and complete in 32 +/- 4 minutes. The inhibitory effects of elastase on Phe contraction were partially reversible. In Ca2+-free (2 mM EGTA) Krebs, Phe caused a small contraction that was not inhibited by elastase, suggesting that elastase does not inhibit Ca2+ release from the intracellular stores. Membrane depolarization by 96 mM KCl, which stimulates Ca2+ entry from the extracellular space, caused a contraction that was inhibited by elastase in a time-dependent and reversible fashion. The reversible inhibitory effects of elastase, particularly in the presence of saturating concentrations of elastin, suggest that they are not due to dissolution of the extracellular matrix or permanent damage to the smooth muscle contractile proteins. Elastase also caused significant inhibition of Phe- and KCl-induced 45Ca2+ influx. These data suggest that elastase promotes aortic relaxation by inhibiting the Ca2+ entry mechanism of vascular smooth muscle contraction, and thus further explain the role of increased elastase activity during the early development of AAA.
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PMID:Elastase promotes aortic dilation by inhibiting Ca2+ influx into vascular smooth muscle. 1508 61

We present the first mathematical model to account for the evolution of the abdominal aortic aneurysm. The artery is modelled as a two-layered, cylindrical membrane using nonlinear elasticity and a physiologically realistic constitutive model. It is subject to a constant systolic pressure and a physiological axial prestretch. The development of the aneurysm is assumed to be a consequence of the remodelling of its material constituents. Microstructural 'recruitment' and fibre density variables for the collagen are introduced into the strain energy density functions. This enables the remodelling of collagen to be addressed as the aneurysm enlarges. An axisymmetric aneurysm, with axisymmetric degradation of elastin and linear differential equations for the remodelling of the fibre variables, is simulated numerically. Using physiologically determined parameters to model the abdominal aorta and realistic remodelling rates for its constituents, the predicted dilations of the aneurysm are consistent with those observed in vivo. An asymmetric aneurysm with spinal contact is also modelled, and the stress distributions are consistent with previous studies.
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PMID:A mathematical model for the growth of the abdominal aortic aneurysm. 1545 32

Vascular smooth muscle cells (VSMCs) synthesize elastin (ELN), major protein of aortic tunica media which confers strength and elasticity to aortic wall. Protein loss or distortion is typical in aneurysm tunica media. Transforming growth factor beta1 (TGFbeta1) inhibits growth and connective protein expression of abdominal VSMCs cultures. Also, in atherogenic studies, estrogen (but not estrogen plus progestin) treatments inhibit aortic collagen accumulation and elastic loss, risk factors to subsequent aortic enlargement. Therefore, polymorphisms of ELN, estrogen receptor alpha (ERalpha) and beta (ERbeta), progesterone receptor (PR) and TGFbeta1 genes and their products may be involved in the abdominal aortic aneurysm (AAA) development. Using PCR-RFLP method, we analyzed ELN RmaI (exon 16), ERalphaPvuII-XbaI (intron 1), ERbetaAluI (exon 8), PR TaqI (intron 7) and TGFbeta1 Bsu36I (-509 bp, promoter) polymorphisms in 324 Caucasian male subjects: 225 healthy controls (mean age 71.20 +/- 6.85 years) and 99 unrelated AAA patients (mean age 69.8 +/- 7.1 years). No difference in ELN, ERalpha, PR and TGFbeta1 allele frequencies was observed in AAA patients versus controls (P > 0.05). However, because possessing at least an ERbetaAluI restriction site was statistically associated to AAA onset (chi(2) = 5.220; OR = 1.82, P < 0.05), ERbeta polymorphism was proposed as genetic determinant in the AAA susceptibility.
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PMID:Allelic genes involved in artery compliance and susceptibility to sporadic abdominal aortic aneurysm. 1569 46

The rat model of abdominal aortic aneurysm (AAA) is associated with inflammation, destruction of extracellular matrix, and production of both inducible nitric oxide synthase (iNOS) and matrix metalloproteinase-9 (MMP-9). Indomethacin, a nonselective cyclooxygenase inhibitor, may prevent AAA formation by inhibiting cyclooxygenase-2 (COX-2) activity. We hypothesized that indomethacin, rofecoxib (selective COX-2 inhibitor), and 1400 W (selective iNOS activity inhibitor) would decrease aneurysm formation in the rat model. Forty-six male Wistar rats underwent intraaortic elastase infusion in two parallel studies based on medication delivery route. Sixteen rats were randomized to rofecoxib or water by gastric lavage. Thirty rats were randomized to subcutaneous saline, indomethacin, or 1400 W. Heart rate, blood pressure and aortic diameters were measured. Western Blot and mRNA analysis for MMP-9 and iNOS was performed on postoperative day 7 aortic segments. Elastin degradation and inflammation were evaluated by immunohistochemistry. Elastase infusion produced AAA in all rats. 1400 W significantly limited aneurysm expansion (p = 0.01) whereas treatment with indomethacin and rofecoxib did not. Only 1400 W significantly increased blood pressure (p < 0.001). Indomethacin alone statistically decreased MMP-9 (p < 0.011). 1400 W resulted in greater conservation of aortic elastin than indomethacin (p = 0.025). All groups demonstrated statistically similar expression of iNOS. In conclusion, selective iNOS activity inhibitor, 1400 W, significantly decreased aneurysm size and preserved aortic elastin without altering MMP-9 levels. Indomethacin significantly decreased MMP-9 expression without decreasing aneurysm size. Rofecoxib did not significantly decrease MMP-9 expression or aneurysm size. Inhibition of iNOS limits aneurysmal expansion by mechanisms other than MMP-9 inhibition. MMP-9 inhibition by indomethacin is not sufficient to limit aneurysm expansion in our model.
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PMID:Suppression of experimental aortic aneurysms: comparison of inducible nitric oxide synthase and cyclooxygenase inhibitors. 1577 Mar 65

There are significant associations between moderate increases in serum homocysteine and three cardiovascular diseases: ischemic heart disease, deep vein thrombosis and pulmonary embolism, and stroke. An association between the presence of abdominal aortic aneurysm and elevated homocysteine plasma levels has been indicated. Although chronic systemic hypertension is the most common factor predisposing the aorta to dissection, homocysteinemia has never been known as the risk for aortic dissection except for that with Marfan syndrome. Homocysteinemia is suggested to be the risk for aortic dissection in Marfan syndrome and spontaneous cervical artery dissection. Reduced fibrillin-1 deposition into the extracellular matrix is found not only in Marfan syndrome but also in isolated ascending aortic aneurysm and dissection. The reduced matrix deposition produces a mild form of weakness of elastic tissue, which predisposes to ascending aortic aneurysm and dissection in patients who do not have the Marfan syndrome. The defect in fibrillin-1 leads to: (1) formation of elastin that is abnormally aggregated and more easily degraded by matrix metalloproteinases than is normal elastin; (2) upregulation of the synthesis of matrix metalloproteinases; (3) progressive destruction of connective tissue by these enzymes; (4) development of thoracic aortic aneurysms. Homocysteine causes premature breakdown in the arterial elastic fibers by activation of the elastolytic activities. Irreversible homocysteinylation of long-lived proteins should lead to cumulative damage and progressive clinical manifestations, and fibrillin-1 is seen as the paradigm of extracellular connective tissue proteins that are specially susceptible to homocysteine (and presumably homocysteine thiolactone) attack. The authors hereupon propose a novel hypothesis that homocysteine plays an important role in development of aortic dissection and that homocysteinemia is one of the risk factors for aortic dissection.
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PMID:Homocysteinemia is a risk factor for aortic dissection. 1578 May 1

Abdominal aortic aneurysm (AAA) is a complex remodeling process that involves both synthesis and degradation of extracellular matrix proteins in the aortic wall, leading to decreased tensile strength, progressive dilation and eventual rupture. Chronic inflammation, increased local production of elastin-degrading proteases by inflammatory cells and destruction of medial elastic lamellae play important roles in aneurysm progression. Neovascularization in all layers of the arterial wall is prominent and angiogenesis can facilitate chronic inflammation. It is still unclear what initiates aneurysmal dilation and what determines its progression. The complex nature of the process has defied elucidation. Apart from macrophages, the predominant immune cell infiltrates reported so far are CD3(+)T cells that express CD4 and CD8. Infiltrates of type 2 Th cells and their production of IL-4 and IL-5 have been implicated in AAA development. However, NKT and NK cells have a Th0 cytokine profile and can also produce type 2 as well as type 1 (IL-2 and IFNgamma) cytokines. We have demonstrated the presence of NK and NKT cells in AAA tissue. With their growing importance in autoimmunity and transplantation, they may play a role in AAA development. Therefore, there is a need to use a combination of T and NK markers to fully characterize both innate and adaptive lymphoid cell subsets in local inflammatory infiltrates in order to elucidate their roles in AAA progression.
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PMID:Predominance of Th2 response in human abdominal aortic aneurysm: mistaken identity for IL-4-producing NK and NKT cells? 1596 67

The cysteine protease cathepsin L is one of the most potent mammalian elastases and collagenases, widely expressed at basal levels in most tested tissues and cell types, and regulated by pro-inflammatory stimuli. The inflammatory arterial diseases abdominal aortic aneurysm (AAA) and atherosclerosis involve extensive vascular remodeling that requires elastolysis and collagenolysis. This study examined the hypothesis that cathepsin L is over-expressed in human AAA and atherosclerotic lesions and its expression in vascular cell types found in these lesions is regulated by pro-inflammatory cytokines. Immunohistochemical and tissue extract immunoblot analysis demonstrated increased expression of cathepsin L in human AAA and atheromata and localized its expression to lesional smooth muscle cells (SMC), endothelial cells (EC), and macrophages. In primary cultured human SMC, EC, and monocyte-derived macrophages, pro-inflammatory cytokines or growth factors induced the expression of cathepsin L and its activity against extracellular collagen and elastin. Patients with coronary artery stenosis (n=65) had higher serum cathepsin L levels than those without lesions detectable by quantitative coronary angiography (n=30) (1.47+/-0.33 ng/ml versus 0.60+/-0.06 ng/ml, p<0.02). A strong correlation between the percent of stenosis of left anterior descending coronary artery and serum cathepsin L levels in patients with stenosis (R=0.542, p<0.0001), also suggests involvement of cathepsin L in these vascular diseases.
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PMID:Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells. 1598 60

Abdominal aortic aneurysm (AAA) is characterized by dilatation of arterial walls, which is accompanied by degradation of elastin and collagen molecules. Biochemical and environmental factors are known to be relevant for AAA development, and familial predisposition is well recognized. A connective tissue disorder that is also associated with fragmentation of elastic fibers is Pseudoxanthoma elasticum (PXE). PXE is caused by mutations in the ABCC6 gene and mainly affects dermal, ocular and all vascular tissues. To investigate whether variations in ABCC6 are found in AAA patients and to determine mutations in PXE patients, we analyzed seven selected ABCC6 exons of 133 AAA and 54 PXE patients subjected to mutational analysis. In our cohort of AAA patients, we found five ABCC6 alterations, which result in missense or silent amino acid variants. The allelic frequencies of these sequence variations were not significantly different between AAA patients and healthy controls. Therefore, we suggest that alterations in ABCC6 are not a genetic risk factor for AAA. Mutational screening of the PXE patients revealed 19 different ABCC6 variations, including two novel PXE-causing mutations. These results expand the ABCC6 mutation database in PXE.
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PMID:Analysis of sequence variations in the ABCC6 gene among patients with abdominal aortic aneurysm and pseudoxanthoma elasticum. 1612 78

The abdominal aortic aneurysm (AAA) wall represents an extreme example of arterial remodeling with disturbed elastin, collagen and proteoglycan metabolism. The aim of this study was to evaluate enzymes involved in the degradation of glycosaminoglycan chains and core proteins of proteoglycans in the AAA wall. The study material consisted of wall samples from 10 AAA. Fragments of 5 normal abdominal aortas from organ donors were used as a control. The activity of endoglycosidases, exoglycosidases and sulfatases was measured using colorimetric methods. To assess matrix metalloproteinases (MMPs), Western blot and zymography were performed. The activity of endoglycosidase degrading chondroitin-4-sulfate was lower in the AAA wall. Endoglycosidase degrading heparan sulfate and dermatan sulfate, arylosulfatase B, as well as all the exoglycosidases assessed demonstrated higher activities in the AAA wall. Furthermore, increased expression of MMP1, MMP2 and MMP9 was also shown in the AAA wall. Zymography revealed decreased activity of pro-MMP2 and presence of pro-MMP9 in the AAA wall compared to the wall of normal aorta. Extensive changes in the activity of glycosaminoglycan-degrading enzymes and MMPs may influence the organization of the extracellular matrix network and lead to previously demonstrated changes in the proteoglycan and glycosaminoglycan content in the AAA wall.
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PMID:Evaluation of enzymes involved in proteoglycan degradation in the wall of abdominal aortic aneurysms. 1629 69

Abdominal aortic aneurysm (AAA) is one of the major vascular diseases caused by atherosclerosis. Because treatment for AAA mainly consists of surgery to prevent deaths from AAA rupture and there is a conspicuous absence of alternative therapeutic strategies, the development of minimally invasive treatment is needed. To develop a novel therapeutic approach, we examined the simultaneous inhibition of the transcription factors NFkappaB and ets, which regulate inflammation and matrix degradation, in a rabbit AAA model. In this study, we employed chimeric decoy oligodeoxynucleotides (ODN), containing the consensus sequences of both the NFkappaB- and ets-binding sites, to inhibit both the transcription factors simultaneously. Using a delivery sheet, we examined the inhibitory effect of chimeric decoy ODN on aortic dilatation. Ultrasound and angiographic analysis demonstrated that treatment with chimeric decoy ODN significantly prevented the progression of elastase-induced aortic dilatation. The inhibitory effect of chimeric decoy ODN on aortic dilatation was also confirmed by histological studies. Treatment with chimeric decoy ODN reduced the activities of matrix metalloproteinase (MMP)-2 and MMP-9 and markedly inhibited the proteolysis of elastin as compared to scrambled decoy ODN. Interestingly, treatment with chimeric decoy ODN also suppressed VCAM-1 and MCP-1 gene expression, leading to inhibition of macrophage infiltration in the adventitia and media. The present study in a rabbit model provides a novel strategy to treat AAA by the simultaneous inhibition of both NFkappaB and ets using chimeric decoy ODN. Further modification of chimeric decoy ODN would be useful to treat AAA as a decoy-based therapy.
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PMID:Prevention of abdominal aortic aneurysms by simultaneous inhibition of NFkappaB and ets using chimeric decoy oligonucleotides in a rabbit model. 1639 9


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