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 risk of rupture of an abdominal aortic aneurysm increases with aortic diameter. To obtain insight into the pathological processes associated with the vascular remodeling that accompanies aortic dilatation, we compared the histological features and the activity of matrix metalloproteinases (MMPs) in biopsies from 21 small (4.0 to 5.5 cm in diameter) and 45 larger abdominal aortic aneurysms. The histological feature most clearly associated with enlarging aneurysm diameter was a higher density of inflammatory cells in the adventitia, P = .018. This inflammation was nonspecific, principally macrophages and B lymphocytes. Fibrosis of the adventitia provided compensatory thickening of the aortic wall as the aneurysm diameter increased. A combination of zymography and immunoblotting identified gelatinase A (MMP-2) as the principal metallogelatinase in small aneurysms, whereas zymography indicated an increasing activity of gelatinase B (MMP-9) in large aneurysms. Homogenates prepared from both small and large aneurysms had similar total activity against gelatin or type IV collagen. However, the concentration of gelatinase A, determined by immunoassay, was highest for small aneurysms: median concentrations, 385, 244, and 166 ng/mg protein for small aneurysms, large aneurysms, and atherosclerotic aorta, respectively. Immunolocalization studies indicated that gelatinase A was concentrated along fibrous tissue of both the acellular media and the atherosclerotic plaque. The recruitment of inflammatory cells into the adventitia, with subsequent elaboration of metalloproteinases, including gelatinase B, may contribute to the rapid growth and rupture of larger aneurysms.
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PMID:Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. 762 8

Degradation of extracellular matrix, especially elastin, within the aortic wall is a hallmark of abdominal aortic aneurysms (AAAs). Normal turnover of matrix proteins is mediated by a family of enzymes called matrix metalloproteinases (MMPs). MMP activity is regulated by proteins called tissue inhibitors of metalloproteinases (TIMPs). We analyzed the expression of all known MMPs with established elastolytic activity and TIMPs in human AAA and control tissue. mRNA coding for MMP-9, MMP-2, human macrophage metalloelastase, MMP-7, TIMP-1, and TIMP-2 were amplified by reverse transcriptase-PCR in control and AAA tissue. A Northern blot assay was used to measure the levels of mRNA coding for MMP-2, MMP-9, TIMP-1, and TIMP-2. Control aortic tissue was obtained from patients with occlusive disease and from organ donors. The expression of MMP-7 and human macrophage metalloelastase was not detected in any aortic specimens. By Northern blot analysis the mean level of MMP-2 mRNA was not significantly different between control groups and AAAs (normalized values: occlusive, 1.5 +/- 0.8, n = 3; donor, 4.5 +/- 2.2, n = 6; AAA, 4.0 +/- 0.95, n = 15). There was a significant increase in the level of MMP-9 mRNA in AAA specimens (occlusive, 16.8 +/- 3, n = 3; donor, 5.7 +/- 1.2, n = 6; AAA, 56.7 +/- 11, n = 15, p = 0.0069). The levels of mRNA coding for TIMP-1 were not significantly different. There was a small but statistically significant increase in TIMP-2 mRNA in AAA tissue. These data support the hypothesis that increased activity of MMP-9, but not MMP-2, is an important factor in the etiology of AAAs. This enhanced MMP-9 activity could then result in degradation of the ECM, leading to aneurysmal dilatation.
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PMID:Expression of matrix metalloproteinases and TIMPs in human abdominal aortic aneurysms. 1007 71

Degradation of the elastic media is a hallmark of abdominal aortic aneurysms (AAAs). We examined the expression of 2 elastolytic matrix metalloproteinases (MMPs), MMP-2 and MMP-9, in AAA aortic tissues compared with those from atherosclerotic occlusive disease (AOD) and nondiseased control tissues. Quantitative competitive reverse transcription-polymerase chain reaction and gelatin zymography showed increased MMP-9 mRNA and protein in both AAA and AOD tissues compared with those in control tissue, but there was no significant difference between AAA and AOD. In contrast, MMP-2 mRNA and protein levels were significantly higher in AAA than in AOD or control tissues. Sequential extraction of the MMPs from the aortic tissue with a physiological salt solution, 2% dimethylsulfoxide (DMSO), and 10 mol/L urea showed that large amounts of MMP-2 and MMP-9 were bound to the matrix. The most conspicuous finding was that the levels of MMP-2 were significantly elevated in the DMSO fraction in AAA tissues compared with AOD and control tissues. In addition, a large portion of MMP-2 found in the DMSO and urea fractions was in the active 62-kDa form, indicating that the precursor of MMP-2 in AAA is largely activated locally and binds to the tissue matrix tightly. By immunolocalization, MMP-9 was found to be primarily produced by macrophages and MMP-2 by mesenchymal cells. The production of MMP-2 was prominent when mesenchymal cells were surrounded by inflammatory cells, suggesting paracrine modulation of MMP-2 expression in AAAs. These observations emphasize that MMP-2 participates in the progression of AAAs by degrading aortic tissue matrix components.
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PMID:Matrix metalloproteinase-2 production and its binding to the matrix are increased in abdominal aortic aneurysms. 976 36

Abdominal aortic aneurysms (AAAs) represent a chronic degenerative condition associated with a life-threatening risk of rupture. The evolution of AAAs is thought to involve the progressive degradation of aortic wall elastin and collagen, and increased local production of several matrix metallo-proteinases (MMPs) has been implicated in this process. We have previously shown that tetracycline derivatives and other MMP inhibitors suppress aneurysm development in experimental animal models of AAA. Doxycycline also reduces the expression of MMP-2 and MMP-9 by human vascular wall cell types and by AAA tissue explants in vitro. To determine whether this strategy might have a role in the clinical management of small AAA, we examined the effect of doxycycline on aortic wall MMP expression in vivo. Patients were treated with doxycycline (100 mg p.o. bid) for 7 days prior to elective AAA repair, and aneurysm tissues were obtained at the time of surgery (n = 5). Tissues obtained from an equal number of untreated patients with AAA were used for comparison. By reverse transcription-polymerase chain reaction and Southern blot analysis, MMP-2 and MMP-9 were both found to be abundantly expressed in the aneurysm wall. Preoperative treatment with doxycycline was associated with a 3-fold reduction in aortic wall expression of MMP-2 and a 4-fold reduction in MMP-9 (p < 0.05 compared to untreated AAA). These preliminary results suggest that even short-term treatment with doxycycline can suppress MMP expression within human AAA tissues. Given its pleiotropic effects as an MMP inhibitor, doxycycline may be particularly effective in suppressing aortic wall connective tissue degradation. While it remains to be determined whether MMP inhibition will have a clinically significant impact on aneurysm expansion, it is expected that this question can be resolved by a properly designed prospective randomized clinical trial.
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PMID:MMP inhibition in abdominal aortic aneurysms. Rationale for a prospective randomized clinical trial. 1041 28

Abdominal aortic aneurysms (AAAs) are characterized by structural alterations of the aortic wall resulting from degradation of collagen and elastin. Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, show strong elastinolytic activity. We examined the levels of mRNA for MMP-2, MMP-9, membrane type (MT)-MMP-1, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 in AAAs (n = 8), atherosclerotic occlusive diseases (AOD) (n = 8), and normal subjects (n = 8) using the reverse transcription-polymerase chain reaction (RT-PCR). We also analyzed the gelatinolytic activity of these metalloproteinases using gelatin zymography. The levels of MMP-2 and MMP-9 mRNA were increased in the AAA group compared with those in the AOD group and normal subjects. The levels for TIMP-1 and TIMP-2 mRNA in the AAA group were also higher than those in the AOD and normal groups. Only in the case of MT-MMP-1 was the difference between AAA and AOD not statistically significant. By gelatin zymography with the same samples used for RT-PCR, gelatinolytic activity of MMP-9 was elevated in all AAA tissues. The 62-kDa form of MMP-2 was elevated in both the AAA and AOD groups and did not differ significantly between them. Linear regression analysis demonstrated a significant positive correlation between mRNA levels of MMPs and those of TIMPs. These observations suggest that aneurysm formation in patients with atherosclerosis is related to the degree of MMP-9 expression.
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PMID:Enhanced expression of matrix metalloproteinase-9 in abdominal aortic aneurysms. 1134 73

Matrix metalloproteinases (MMPs) 9 and 2 are increased in human abdominal aortic aneurysm (AAA) tissue, but their precise role and potential interaction remain unclear. Experimental induction of aortic aneurysms in mice genetically deficient in these peptidases could provide new insight into AAA pathogenesis. Mice deficient in the expression of MMP-9 (MMP-9KO) or MMP-2 (MMP-2KO) and their corresponding wild-type background mice (WT) underwent AAA induction by abluminal application of calcium chloride (CaCl(2)). No aneurysm formation was observed at 10 weeks after treatment in either the MMP-9KO or the MMP-2KO mice, whereas the corresponding WT mice showed an average 74% and 52% increase in aortic diameter, respectively. Reinfusion of competent macrophages from the corresponding WT strains into knockout mice resulted in reconstitution of AAA in MMP-9KO but not MMP-2KO mice. These findings suggest that macrophage-derived MMP-9 and mesenchymal cell MMP-2 are both required and work in concert to produce AAA.
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PMID:Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. 1220 61

Medial degeneration of extracellular matrix (ECM) proteins in the wall of abdominal aortas results in smooth muscle cell destruction, a loss of architectural integrity, and abdominal aortic aneurysm (AAA) formation. It has been theorized that an imbalance between proteinases and their naturally occurring inhibitors is the cause of these observed histologic abnormalities. Therefore, the purpose of this investigation was to determine if differences in the matrix metalloproteinase (MMP) -2 and -9, tissue inhibitor of metalloproteinase-1 (TIMP-1), tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA) protein and activity levels existed between infrarenal AAA and normal abdominal aortic tissue specimens. Between November 1995 and January 1997, 10 patients undergoing elective infrarenal AAA repair had a portion of their aneurysm walls snap frozen in liquid nitrogen and processed for subsequent western blot or zymographic analysis. Tissue specimens from 6 normal abdominal aortas obtained from fresh cadaver specimens were similarly processed and served as controls. Protein levels for MMP-2, MMP-9, TIMP-1, uPA, and tPA were analyzed by western blotting. The degree of MMP-2 and MMP-9 gelatinolytic activity was analyzed by zymography. Detection and immunolocalization for MMP-2, MMP-9 and CD68 was performed on tissue sections of AAA and normal infrarenal abdominal aortas fixed in 10% formalin. MMP-9 and tPA protein levels were increased in AAAs compared to controls by western blotting. However, uPA levels were slightly increased in controls. No differences in TIMP-1 protein levels were identified. Similarly, zymography demonstrated increased MMP-2 and MMP-9 gelatinolytic activity in AAAs compared to controls (p < or = 0.05). CD68-positive cells (macrophages) in the adventitia and media demonstrated immunoreactivity to MMP-9. This investigation demonstrated increased MMP-9 proteinase activity and tPA protein levels in the walls of AAAs, as well as inflammatory leukocyte invasion of the adventitia and media compared to controls. These data suggest that leukocyte-derived MMP-9 is associated with aortic wall degeneration and aneurysm formation. Furthermore, activation of MMP-9 may be caused by increased tPA levels in the walls of AAAs.
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PMID:Matrix metalloproteinase expressions in arteriosclerotic aneurysmal disease. 1270 18

Osteopontin (OPN) is expressed in atherosclerotic lesions, particularly in diabetic patients. To determine the role of OPN in atherogenesis, ApoE-/-OPN+/+, ApoE-/-OPN+/-, and ApoE-/-OPN-/- mice were infused with Ang II, inducing vascular OPN expression and accelerating atherosclerosis. Compared with ApoE-/-OPN+/+ mice, ApoE-/-OPN+/- and ApoE-/-OPN-/- mice developed less Ang II-accelerated atherosclerosis. ApoE-/- mice transplanted with bone marrow derived from ApoE-/-OPN-/- mice had less Ang II-induced atherosclerosis compared with animals receiving ApoE-/-OPN+/+ cells. Aortae from Ang II-infused ApoE-/-OPN-/- mice expressed less CD68, C-C-chemokine receptor 2, and VCAM-1. In response to intraperitoneal thioglycollate, recruitment of leukocytes in OPN-/- mice was impaired, and OPN-/- leukocytes exhibited decreased basal and MCP-1-directed migration. Furthermore, macrophage viability in atherosclerotic lesions from Ang II-infused ApoE-/-OPN-/- mice was decreased. Finally, Ang II-induced abdominal aortic aneurysm formation in ApoE-/-OPN-/- mice was reduced and associated with decreased MMP-2 and MMP-9 activity. These data suggest an important role for leukocyte-derived OPN in mediating Ang II-accelerated atherosclerosis and aneurysm formation.
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PMID:Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice. 1459 59

Degradation of the extracellular matrix components elastin and collagen has been implicated in vascular diseases, including abdominal aortic aneurysm (AAA) and atherosclerotic plaque rupture. Increased expression of matrix metalloproteinases (MMPs) is involved in these disease processes. Our previous studies have demonstrated that MMP-2 derived from mesenchymal cells is required for aneurysm development in a murine model. Doxycycline is a nonspecific inhibitor of MMPs. In the present study, the mechanisms of the inhibitory effects of doxycycline on MMP-2 expression from cultured human aortic smooth muscle cells (SMCs) and human aortic aneurysm tissue explants were studied. Doxycycline inhibited MMP-2 expression from cultured SMCs in a concentration-dependent manner (5-40 microg/mL; inhibitory concentration of 50%, 6.5 microg/mL). At normal therapeutic serum concentration (5 microg/mL) doxycycline significantly reduced MMP-2 production from SMCs (37%; P <.05), which were stimulated with conditioned media from macrophage or lymphocyte co-culture simulating the inflammatory milieu of AAA tissue. This correlated with a decrease in MMP-2 mRNA half-life, from 49 hours to 28 hours, which suggests that doxycycline inhibits SMC MMP-2 production in part by reducing MMP-2 mRNA stability. When AAA tissue was cultured for 10 days with doxycycline at concentrations of 2.5 to 40 microg/mL, the media exhibited a concentration-dependent decrease in both active and latent forms of MMP-2 and MMP-9. Doxycycline at a concentration of 5 microg/mL reduced active and latent MMP-2 secreted from cultured AAA tissue by 50% and 30%, respectively (P <.05). These study findings demonstrate that doxycycline at standard therapeutic serum concentrations inhibits MMP-2 expression from cultured human aortic SMCs and AAA tissue explants. Inasmuch as MMP activity contributes to extracellular matrix degradation in AAAs and atherosclerotic plaque, doxycycline may have potential value in treating these diseases.
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PMID:Mechanism of inhibition of matrix metalloproteinase-2 expression by doxycycline in human aortic smooth muscle cells. 1468 44

Our objective was to examine the role of an exogenous nitric oxide (NO) donor, DETA-NONOate (DETA), on matrix metalloproteinase (MMP)-9, MMP-2, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 expression and activity in interleukin (IL)-1beta-induced rat aortic smooth muscle cells (RA-SMCs) and rat aortic explants (RAEs). RA-SMCs were incubated with IL-1beta (2 ng/ml), an inflammatory cytokine known to induce MMP-9 expression, and increasing concentrations of DETA (0, 1.0, 10, 100 microM; n = 3/group) for 48 hr. RAEs were incubated with IL-1beta (2 ng/mL) and increasing concentrations of DETA (0, 5.0, 50, 100, and 500 microM; n = 3/group) for 48 hr. Media were collected and assayed for NO(x) by the Griess reaction and MMP-9 activity by zymography. Messenger RNA (mRNA) was extracted from cells and analyzed for MMP-9, MMP-2, and TIMP-1 expression levels by quantitative real-time reverse-transcriptase polymerase chain reaction. All statistical analyses were performed by analysis of variance. In RA-SMCs and RAEs, DETA administration resulted in a dose-dependent increase in media NOx concentration (RA-SCM p < 0.01, RAE p < 0.01) and a concurrent decrease in both MMP-9 expression (RASMC p = 0.01, RAE p = 0.01) and activity (RASMC p = 0.04, RAE p = 0.006). There were no significant differences seen in MMP-2 and TIMP-1 expression or activity in response to DETA exposure. DETA decreased IL-1beta-induced MMP-9 expression and activity in both RA-SMCs and RAEs in a dose-dependent fashion. In addition, DETA administration had no effect on MMP-2 or TIMP-1 expression or activity in vitro. These data suggest that NO donors may be beneficial in decreasing MMP-9 levels and might serve to inhibit MMP-9-dependent vessel wall remodeling seen during abdominal aortic aneurysm formation.
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PMID:The nitric oxide donor DETA-NONOate decreases matrix metalloproteinase-9 expression and activity in rat aortic smooth muscle and abdominal aortic explants. 1637 39


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