(Circulation. 1999;100:48-54.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Inhibition of Prostaglandin E2 Synthesis in Abdominal Aortic Aneurysms
Implications for Smooth Muscle Cell Viability, Inflammatory Processes, and the Expansion of Abdominal Aortic Aneurysms
From the Department of Vascular Surgery at Charing Cross and the Department of Clinical Pharmacology at Hammersmith Imperial College School of Medicine (G.W.T.), London, UK.
Correspondence to J.T. Powell, Vascular Surgery, Charing Cross Hospital, Fulham Palace Rd, London W6 8RF, UK. E-mail j.powell{at}ic.ac.uk
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Abstract |
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Background—There is no treatment proven to limit the growth of abdominal aortic aneurysms, in which the histological hallmarks include inflammation and medial atrophy, with apoptosis of smooth muscle cells and destruction of elastin.
Methods and Results—Aneurysm biopsies were used for explant cultures, the preparation of smooth muscle cell cultures, and isolation of macrophages. Tissue macrophages stained strongly for cyclooxygenase 2. Prostaglandin E2 (PGE2) concentrations in aneurysm tissue homogenates, conditioned medium from explants, and isolated macrophages were 49±22 ng/g, 319±38 ng/mL, and 22±21 ng/mL, respectively. PGE2 inhibited DNA synthesis and proliferation in normal aortic smooth muscle cells (IC50, 23.2±3.8 and 23.6±4.5 ng/mL, respectively). In smooth muscle cells derived from aneurysmal aorta, PGE2 also caused cell death, with generation of oligonucleosomes. Conditioned medium from the mixed smooth muscle and monocyte cultures derived from explants also had potent growth-inhibitory effects, and fractionation of this medium showed that the growth-inhibitory molecule(s) coeluted with PGE2. In explants, indomethacin 10 µmol/L or mefenamic acid 10 µmol/L abolished PGE2 secretion and significantly reduced IL-1ß and IL-6 secretion. In a separate case-control study, the expansion of abdominal aortic aneurysms was compared in 15 patients taking nonsteroidal anti-inflammatory drugs and 63 control subjects; median growth rates were 1.5 and 3.2 mm/y, respectively, P=0.001.
Conclusions—The adverse effects of PGE2 on aortic smooth muscle cell viability and cytokine secretion in vitro and the apparent effect of anti-inflammatory drugs to lower aneurysm growth rates suggest that selective inhibition of PGE2 synthesis could be an effective treatment to curtail aneurysm expansion.
Key Words: aorta • aneurysm • prostaglandins • indomethacin • cyclooxygenase
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Introduction |
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The specific risk factors that cause the abdominal aorta to become aneurysmal in later life have not been identified. Smoking, hypertension, and hypercholesterolemia, identified in epidemiological studies as risk factors for abdominal aortic aneurysm (AAA), are also risk factors for atherosclerosis. No specific causative genes have been identified, although there is a strong familial predisposition to AAA. The 2 histopathological features that discriminate AAA from aortic atherosclerosis without dilatation are (1) medial attenuation, with loss of elastic lamellae, elastin, and smooth muscle cells, and (2) adventitial inflammation.1 2 3 Proteolytic disruption of the tunica media is considered to be an important cause of aortic dilatation.4 5 6
The importance of inflammation as a factor contributing to the
expansion of AAAs has recently been
appreciated.4 7 8 9 Separate studies have shown that
the magnitude of inflammation in the adventitia and the serum
concentration of interferon-
appear to relate to aneurysm
diameter and growth, respectively.4 8 Inflammatory cells
in the adventitia and media, together with the cytokines and
proteolytic enzymes they elaborate, stimulate the continued
proteolysis, with weakening of the aortic wall and aneurysm
expansion. The therapeutic implication of interrupting these processes
is considerable. For instance, in fibroblasts, interleukin (IL)-1ß
increases the expression of matrix metalloproteinases (MMPs), including
MMP-9, and decreases collagen synthesis.10 11
Cyclooxygenase 2, but not
cyclooxygenase 1, is widely expressed in the
aneurysm wall, with concomitant synthesis of
prostaglandin E2
(PGE2), which may have additional effects to
decrease collagen synthesis.11 12
Screening studies have shown that 4% to 5% of men >60 years old have small AAAs (3 to 5 cm in diameter).13 14 Even in these small aneurysms, the inflammatory process appears to be well established.4 8 Most of these small AAAs continue expanding, with annual increases in diameter ranging from 2 to 6 mm/y.15 It is important to find a medical therapy to prevent the expansion of small aneurysms to a size at which prophylactic AAA repair is considered (>5.5 cm in diameter).16 After the success of propranolol in limiting aortic root dilatation in patients with Marfan syndrome,17 the efficacy of propranolol to attenuate AAA growth is being evaluated in clinical trials. Therapy targeted at dampening the inflammatory process in the aneurysm wall might provide an alternative approach.
Our own investigations of inflammatory mediators in the AAA wall were initiated by the observation that when explants of tunica media from AAA were cultured, mononuclear cells appeared to restrict the outgrowth and proliferation of smooth muscle cells. By a process of elimination, our attention became focused on prostanoid metabolites.
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Methods |
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Patients taking nonsteroidal anti-inflammatory drugs, with AAAs 4.0 to 5.5 cm in diameter at presentation, entered locally into the UK Small Aneurysm Study18 and followed up for aneurysm growth for >12 months were identified. These patients (cases) included 12 men and 3 women. Other patients (n=63) matched for age, sex, initial aneurysm diameter, and smoking status were selected as control subjects (controls). Aneurysm diameters were measured by ultrasonography every 3 to 6 months, and growth rates, from a minimum of 3 separate diameter evaluations, were calculated by linear regression analysis. The repeatability of diameter measurement was ±2 mm.
Aneurysm biopsies were obtained from 21 patients (17 male), mean age 70±4 years, at the time of surgical repair from the anterior aneurysm wall of large aneurysms (>5.5 cm) opposite the inferior mesenteric artery and were transported at room temperature to the laboratory in DMEM. After removal of adherent thrombus, full-thickness explant cultures were established with the intima uppermost in 10-cm2 dishes, using 10 mL DMEM/g tissue wet wt. After the tissue had equilibrated for 24 to 48 hours, the medium was replaced and harvested every 48 hours. The first conditioned medium harvested at 96 hours was used for cytokine assays.
Medial explant cultures were established by dissection of the biopsy to obtain the media, which was then cut into 1- to 2-mm3 pieces and placed in explant culture on type I collagen–coated dishes in Cascade medium 231 (Cascade Inc). Culture medium was changed after 7 days and every 2 to 3 days thereafter. Within the first week, mixed cultures comprising smooth muscle cells with varying numbers of adherent mononuclear cells were established. The smooth muscle cells were characterized by staining with anti–smooth muscle cell actin and the mononuclear cells by staining for CD45 (antibodies from Dako). Conditioned medium from these cultures was harvested every third day during the 3- to 4-week period needed to attain confluence. When confluent, smooth muscle cells were transferred (at passage 2 or 3) onto uncoated 24-well or 96-well plates for assessment of metabolic activity, proliferation, and apoptosis.
Macrophage isolation from aortic aneurysm biopsies was
performed by enzymatic dispersion and immunomagnetic separation. Pieces
of tissue (
1 g) were diced into small pieces, 1
mm3, and washed twice in PBS. The washed pieces
were incubated in physiological salt solution (20
mL) containing (in mmol/L) NaCl 130, KCl 6,
CaCl2 0.01, MgCl2 1.2,
glucose 14, and HEPES 10.7, buffered to pH 7.2 with NaOH, plus 2 mg/mL
BSA, 1 mg/mL collagenase type 2, 1 mg/mL
collagenase type 4 (both from Worthington Biochemical
Corp), and 5 mmol/L dithiothreitol, for 12 to 16 hours at 4°C
followed by 2 hours at 37°C. Cells were dispersed by agitation and
washed twice in cold PBS containing 2% FCS before washed
anti-CD14–coated Dynabeads (Dynal Ltd), 7.5 µL, were added to each
tube and incubated with gentle mixing at 4°C for 30 minutes. The
rosetted CD14-positive cells were isolated by placing the tube in a
magnetic particle concentrator, before being resuspended and
washed 4 times in PBS containing 2% FCS (10 mL) before final
suspension in Cascade medium 231 and establishment of cultures
±10 µmol/L indomethacin for 72 hours. The yield
of macrophages ranged from 90 000 to 190 000/g tissue wet wt;
nonspecific esterase staining indicated that 85% of the isolated
cells were viable macrophages.
Smooth muscle cells from normal aorta (an 18-year-old male donor) were purchased from Cascade Biologics Inc, cultured in Cascade medium 231, and used at the fifth or sixth passage.
Saphenous vein endothelial cells at passage 3 were a gift from Suzanne Harley of this laboratory.
MTT assays for mitochondrial activity and 5-bromo-2'-deoxyuridine (BrdU) assays to measure DNA synthesis were performed in 96-well tissue culture plates, using cells at 75% confluence, with triplicate wells for each condition. For MTT assays, cells were treated with test or control medium (200 µL), and MTT in PBS (20 µL, 5 mg/mL) was added to each well for 4 hours. Medium was removed by aspiration, the purple crystalline deposit was dissolved in dimethyl sulfoxide (100 µL), and the absorbance at 570 nm was recorded. For BrdU assays, according to the manufacturer's instructions (Boehringer Mannheim), cells were deprived of serum overnight before addition of test or control medium (200 µL) for the final 24 hours. Results were expressed as a percentage ratio of absorbances for test condition/new medium, and comparisons were made by Student's paired t test.
Cell numbers were determined by counting and acid phosphatase assay. For counting, smooth muscle cells from explant cultures (n=4) were plated onto 6-well tissue culture plates at 6x104 cells/well. The next day, cells were treated with conditioned (n=8 for each experiment) or control medium for 24, 48, and 72 hours, after which, cells were trypsinized and counted in a hemocytometer. Alternatively, cells in 96-well plates were washed twice with cold PBS before the addition of 10 mmol/L p-nitrophenylphosphate in 0.1 mol/L sodium acetate buffer, pH 5.5, containing 0.1% Triton X-100 (125 µL). Plates were incubated at 37°C for 2 hours, the reaction was stopped with 1 mol/L sodium hydroxide (10 µL), and the absorbance was read at 405 nm. Trypsinized cells were used to construct a standard curve.
Apoptosis was assessed by oligonucleosome ELISA
(Calbiochem-Novabiochem) using cells grown in 24-well plates.
Oligonucleosomes were harvested and assayed according to the
manufacturer's instructions. Smooth muscle cells treated with a
cytokine cocktail (tumor necrosis factor [TNF]-
,
interferon [IFN]-, and IL-1ß19 ) provided a positive
control.
Other assays included ELISAs for PGE2 and MMP-9
(Amersham International), IL-1, IL-6, and IFN- (Pelikine, CLB).
Monocyte chemotactic protein (MCP)-1 and TNF- were assayed by
in-house ELISAs. Neutralizing antibodies to IL-6, TNF-, and MCP-1
were obtained from R&D Systems, antibodies to
cyclooxygenases from Santa Cruz and Affiniti, and
prostaglandins A2,
E1, E2, or
F2 from Sigma.
Prostanoid metabolite isolation was performed by solid-phase extraction followed by high-performance liquid chromatography (HPLC). Nonpolar solid-phase bonded silica columns (Amprep octadecyl C18, Amersham International) were used to separate prostanoids from conditioned media into a methanol phase. Columns were prepared by washing with 5 column volumes of methanol, followed by 5 vol distilled water and 5 vol 1% acetic acid. Conditioned medium (5 mL) was passed through the column and washed with 5 vol distilled water. The column was eluted with methanol (2 mL), and the eluate was collected and evaporated to dryness under nitrogen. The products were redissolved in 10% acetonitrile containing 0.04% trifluoroacetic acid, applied to a Nova-Pak C18 column (3.9x150 mm, Waters), and developed with a 10% to 28% gradient of a vol/vol solution of acetonitrile containing 0.04% trifluoroacetic acid.20 [3H]PGE2 (Amersham) was used as a tracer to confirm the elution position of this prostanoid. The liquid phase was removed under vacuum, and the fractions were reconstituted in tissue culture medium and assayed for ability to inhibit BrdU uptake by aortic smooth muscle cells. Initially, 2 sequential fractions were pooled so that the entire elution profile (60x 1-mL fractions) could be assayed in triplicate on a single 96-well plate. Subsequently, single fractions in the area of interest were assayed.
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Results |
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Aortic Smooth Muscle Cell Proliferation Is Limited by Mononuclear Cells
Mixed cultures of smooth muscle cells, always with adherent mononuclear cells, were derived from the medial layer of aneurysm biopsies (Figure 1
, top). Proliferation of the smooth muscle cells appeared to be limited
by the mononuclear cells, which stained positively with antibodies to
CD68 (data not shown).
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Incubation of normal aortic smooth muscle cells (24 hours) in the
medium harvested from these mixed cultures (conditioned medium),
compared with control medium (conditioned by normal aortic smooth
muscle cell cultures), caused a 30% reduction in mitochondrial
activity (MTT test at 4 hours, medium from 13 separate biopsies,
P=0.0001) and almost halved the rate of DNA synthesis
(incorporation of BrdU at 24 hours, n=10, P<0.0001), Table 1. After 48 hours of culture in
conditioned medium, the cell number (acid phosphatase assay) also was
reduced (n=7, P=0.028), and low concentrations of
oligonucleosomes were detected (Table 1).
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Assays were repeated using smooth muscle cells cultured from
aneurysm biopsies, with similar but often accentuated findings
(Table 1
). For example, BrdU incorporation was reduced by
60±20% (n=10, P=0.0001). After 48 hours, the conditioned
medium, compared with control medium, led to net loss of viable cells
(acid phosphatase assay, Table 1). Cell count experiments,
established with 60 000 cells/well, showed cell counts in the controls
(n=4) of 95 000±11 000 at 48 hours and 124 000±12 000 at 72
hours, compared with 87 000±15 000 at 48 hours and 43 000±12 000
at 72 hours in the conditioned medium (n=10). After 48 hours of culture
in conditioned medium, oligonucleosomes were detectable (Table 1).
The conditioned medium did not reduce BrdU or MTT uptake at 24 hours in
human saphenous vein endothelial cell cultures (Table 1). These data suggested that the mononuclear cells of the
cultures secreted component(s) that selectively repressed DNA synthesis
and proliferation of smooth muscle cells and provoked apoptosis
in some cells.
Treatment of Explant Cultures With Indomethacin
Abolishes the Damaging Effects of Conditioned Medium on Cultured Smooth
Muscle Cells
Conditioned media were treated by dialysis or heat
inactivation (80°C, 1 hour) or were prepared in the presence of
indomethacin 10 µmol/L,
NG-monomethyl-L-arginine
(L-NMMA) 1 mmol/L, or glutathione 0.1 mmol/L. The capacity to
diminish BrdU uptake was lost after dialysis or preparation of
conditioned medium in the presence of indomethacin
(n=7) or glutathione (n=4). L-NMMA and heat treatment had no effect on
the toxic component(s) (Table 2).
Neutralizing antibodies to IL-6, MCP-1, TNF-, or IFN- did not
alter the effect of the conditioned medium to reduce BrdU uptake in
cultured smooth muscle cells. These data suggested that the toxic
component(s) secreted by mononuclear cells was an
arachidonic acid metabolite.
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Cyclooxygenase 2 Is Abundantly Expressed in
Aneurysm Tissue, Which Secretes High Concentrations of
PGE2, IL-6, and MCP-1 in Explant Culture
Aneurysm biopsies stained strongly for
cyclooxygenase 2, particularly in
macrophages (Figure 2) and
activated endothelium; staining for
cyclooxygenase 1 was negligible.
Homogenates of aneurysmal tissue also contained
large amounts of PGE2, 49±22 ng/g tissue wet wt
(n=8), whereas homogenates of normal aorta contained <2
ng/g tissue wet wt (n=4). Full-thickness explant biopsies (n=7)
secreted high concentrations of PGE2 (319±38
ng/mL), MCP-1 (71±28 ng/mL), and IL-6 (210±18 ng/mL), with smaller
amounts of IL-1ß (0.166±0.022 ng/mL), Table 3; TNF- and IFN- were not
detected.
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Macrophages Isolated From the Aneurysmal Wall
Secrete PGE2
Macrophages were isolated from aneurysm
biopsies by immunomagnetic separation (Figure 1, bottom). The
isolated macrophages stained strongly for
cyclooxygenase 2 but not for
cyclooxygenase 1 (data not shown).
Macrophage cultures (n=6) secreted PGE2
(5 to 35 ng/mL), this secretion being abolished when cells were
cultured in the presence of indomethacin 10
µmol/L or mefenamic acid 10 µmol/L. Incubation of normal
aortic smooth muscle cells with the macrophage-conditioned
medium, prepared in the presence of indomethacin, had
no effect on BrdU or MTT uptake. In contrast, when prepared in the
absence of indomethacin, the conditioned media (n=4)
caused 46±8% and 30±8% reductions in BrdU and MTT uptake,
respectively. This suggested that a prostanoid metabolite, synthesized
by cyclooxygenase 2 in macrophages, could
impair smooth muscle cell proliferation.
PGE2 Affects Aortic Smooth Muscle Cell
Proliferation
PGA2, PGE1, and
PGF2 1 to 1000 ng/mL or
indomethacin 10 µmol/L had no effect on DNA
synthesis in normal aortic smooth muscle cells, whereas
PGE2 caused a concentration-dependent reduction
in BrdU incorporation after 24 hours (IC50,
23.2±3.8 ng/mL) (Figure 3A).
PGE2 also limited cell proliferation over a
period of 72 hours as measured by acid phosphatase assay in 4 separate
experiments (Figure 3B), but oligonucleosomes were never
detected.
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Similarly, PGE2 (but not
PGA2, PGE1, or
PGF2) caused a concentration-dependent
inhibition of BrdU uptake at 24 hours in smooth muscle cells derived
from aneurysm biopsies (IC50, 6.0±1.6
ng/mL) (Figure 3A). After 72 hours of incubation with
PGE2, cell proliferation was reduced (acid
phosphatase assay: IC50, 21.8±4.4 ng/mL), with a
net decrease in cell numbers at the highest PGE2
concentrations (300 to 1000 ng/mL), in cells from 5 different patients
(Figure 3B). PGE2 increased the number of
oligonucleosomes present in cultures of smooth muscle cells derived
from aneurysm biopsies, with oligonucleosome concentrations
after 48 hours (72 hours) increasing from undetectable levels in the
absence of PGE2 to 0.09±0.05 (0.13), 0.25±0.06
(0.39), and 0.52±0.10 (0.88) U/mL at PGE2
concentrations of 3, 30, and 300 ng/mL, respectively. Insufficient
cells were available from any single patient to conduct a full
concentration-response curve; however, the proportion of
apoptotic cells, even at high concentrations of
PGE2, was only a fraction (10% to 15%) of that
induced by the cytokine cocktail IL-1ß, IFN-, and
TNF-.19
Therefore, PGE2 appears to selectively repress DNA synthesis and cell proliferation in aortic smooth muscle cells cultured from either normal or aneurysmal aorta. In cells derived from aneurysmal aorta, PGE2 may also initiate apoptosis.
Fractionation of Conditioned Medium Suggests That a Prostanoid
Related to PGE2 Represses DNA Synthesis in Aortic Smooth
Muscle Cells
The prostanoids and isoprostanes in the conditioned media were
fractionated by HPLC, and the separate fractions were tested for their
ability to diminish BrdU uptake by normal aortic smooth muscle cells.
The fractions that inhibited the uptake of BrdU eluted at the same
position as [3H]PGE2 in
conditioned medium from 4 separate aneurysm biopsies (Figure 4).
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Use of Nonsteroidal Anti-Inflammatory Drugs Is Associated With
Slower Aneurysm Growth Rates
Suppression of cyclooxygenase 2 activity by
indomethacin or other anti-inflammatory drugs may have
other beneficial effects in the wall of AAAs. First, in full-thickness
aortic explants, indomethacin or mefenamic acid
abolished the very high secretion of PGE2 and
significantly reduced the secretion of IL-1ß and IL-6, although MMP-9
release was unchanged (Table 3). When explants were cultured in
the presence of both indomethacin and exogenous
PGE2 500 ng/mL, the secretion of IL-1ß and IL-6
increased again (Table 3). Second, aneurysm growth rates
were measured in 2 groups of patients with small aneurysms,
cases (n=15) taking nonsteroidal anti-inflammatory drugs (mainly for
joint problems) and controls (n=63) not taking anti-inflammatory drugs;
see Table 4. Systolic blood
pressures were slightly higher in the group taking anti-inflammatory
drugs and plasma cholesterol concentration was slightly
higher in the controls, but these differences were far from
significant. The usage of other drugs, including diuretics,
calcium channel blockers, other antihypertensive drugs, and
lipid-lowering drugs, was not different between the 2 groups. Low-dose
aspirin (75 mg/d) was taken by 3 of 15 patients taking
anti-inflammatory drugs and 21 of 63 patients not taking these drugs.
Only 11 patients took ß-blockers, 3 of these among the cases; no
patient took propranolol. The median aneurysm
growth rate in the cases was 1.5 mm/y compared with 3.2 mm/y
in controls, P=0.001 (Mann-Whitney U test),
Figure 5.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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PGE2, which is synthesized at high concentration in the walls of AAAs, appears to have adverse effects in vitro on both proliferation of aortic smooth muscle cells and cytokine secretion by the aneurysm wall. The possibility that PGE2 has a pivotal role in the dilatation of AAAs is accentuated by our finding, from a small case-control study, that usage of nonsteroidal anti-inflammatory drugs was associated with slower aneurysm growth rates.
We have shown that outgrowth of smooth muscle cells from explants of AAA biopsies appears to be limited by an arachidonate metabolite, probably macrophage-derived PGE2. PGE2 also inhibited DNA synthesis and proliferation of smooth muscle cells cultured from normal and aneurysmal aorta. Other prostaglandins tested were ineffective. Specific receptors for PGE2 in aortic smooth muscle cells may mediate these effects, with EP1 receptors being described as having higher affinity for PGE2 than PGE1.21 The differential expression of EP receptors in smooth muscle cells from young healthy aorta and cells from AAAs could be sufficient to explain why PGE2 caused cell death, probably by apoptosis, only in cells derived from aneurysmal aorta. The apparent concentration of PGE2 in homogenates of aneurysmal aorta (49±22 ng/mL) was of the same order of magnitude as its IC50 for inhibiting cell proliferation (24±5 ng/mL). In culture, however, as in vivo, PGE2 may be metabolized to isoprostanes, cross-reacting with antibodies used to assay PGE2. Therefore, either PGE2 or its metabolic products may exert adverse effects on aortic smooth muscle cell proliferation and viability in vivo.
Macrophages in and from the AAA wall stain strongly for
cyclooxygenase 2 but not
cyclooxygenase 1, which confirms previous
findings.12 Therefore, the effects of
indomethacin or mefenamic acid (which is relatively
more selective for cyclooxygenase 2 than
cyclooxygenase 1 in vivo22 ) on explant
and cell cultures must be attributed to inhibition of
cyclooxygenase 2. The low concentrations of drugs
used (10 µmol/L) and the reversal of their effects by exogenous
PGE2 diminished the possibility that these drugs
were acting as PPAR- agonists.23 In short-term explant
cultures, both indomethacin and mefenamic acid rapidly
repressed the secretion of PGE2 and diminished
the secretion of IL-1ß and IL-6. Alterations in MMP-9 expression and
release may be a later event, which unfortunately cannot be studied
during the limited period of explant viability. The effects of
nonsteroidal anti-inflammatory drugs to suppress cytokine
secretion could have long-term benefits by reducing both inflammation
and proteolysis in the AAA wall. These mechanisms are likely to
contribute to the apparent effect of nonsteroidal anti-inflammatory
drugs to halve the rate of aneurysm expansion. This observation
requires confirmation from a randomized trial using selective
cyclooxygenase 2 inhibitors.
These studies have highlighted both the detrimental effects that excessive production of PGE2 could have in the aneurysm wall and the potential benefits of inhibition of cyclooxygenase 2 inhibition for the patient with a small AAA.
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Acknowledgments |
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This work was supported by the British Heart Foundation. We thank all the vascular surgeons of the Imperial College School of Medicine Hospitals who provided aneurysm biopsies.
Received February 23, 1999; revision received April 9, 1999; accepted April 15, 1999.
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A. Maleszka, G. Kleikamp, A. Zittermann, M. R.G. Serrano, and R. Koerfer Simultaneous Aortic and Mitral Valve Replacement in Octogenarians: A Viable Option? Ann. Thorac. Surg., December 1, 2008; 86(6): 1804 - 1808. [Abstract] [Full Text] [PDF]
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 M. Wang, E. Lee, W. Song, E. Ricciotti, D. J. Rader, J. A. Lawson, E. Pure, and G. A. FitzGerald Microsomal Prostaglandin E Synthase-1 Deletion Suppresses Oxidative Stress and Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Circulation, March 11, 2008; 117(10): 1302 - 1309. [Abstract] [Full Text] [PDF]
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J. M. Gitlin, D. B. Trivedi, R. Langenbach, and C. D. Loftin Genetic deficiency of cyclooxygenase-2 attenuates abdominal aortic aneurysm formation in mice Cardiovasc Res, January 1, 2007; 73(1): 227 - 236. [Abstract] [Full Text] [PDF]
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 J. Golledge, J. Muller, A. Daugherty, and P. Norman Abdominal Aortic Aneurysm: Pathogenesis and Implications for Management Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2605 - 2613. [Abstract] [Full Text] [PDF]
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E. Choke, M. M. Thompson, J. Dawson, W. R. W. Wilson, S. Sayed, I. M. Loftus, and G. W. Cockerill Abdominal Aortic Aneurysm Rupture Is Associated With Increased Medial Neovascularization and Overexpression of Proangiogenic Cytokines Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): 2077 - 2082. [Abstract] [Full Text] [PDF]
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D. Bishop-Bailey, J. A. Mitchell, and T. D. Warner COX-2 in cardiovascular disease. Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 956 - 958. [Full Text] [PDF]
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V. L. King, D. B. Trivedi, J. M. Gitlin, and C. D. Loftin Selective Cyclooxygenase-2 Inhibition With Celecoxib Decreases Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1137 - 1143. [Abstract] [Full Text] [PDF]
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J. Dai, F. Losy, A.-M. Guinault, C. Pages, I. Anegon, P. Desgranges, J.-P. Becquemin, and E. Allaire Overexpression of Transforming Growth Factor-{beta}1 Stabilizes Already-Formed Aortic Aneurysms: A First Approach to Induction of Functional Healing by Endovascular Gene Therapy Circulation, August 16, 2005; 112(7): 1008 - 1015. [Abstract] [Full Text] [PDF]
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 J. Rodel, D. Prochnau, K. Prager, J. Baumert, K.-H. Schmidt, and E. Straube Chlamydia pneumoniae Decreases Smooth Muscle Cell Proliferation through Induction of Prostaglandin E2 Synthesis Infect. Immun., August 1, 2004; 72(8): 4900 - 4904. [Abstract] [Full Text] [PDF]
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 E. F. Steinmetz, C. Buckley, and R. W. Thompson Prospects for the Medical Management of Abdominal Aortic Aneurysms Vascular and Endovascular Surgery, May 1, 2003; 37(3): 151 - 163. [Abstract] [PDF]
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 I. Loftus and M. Thompson The role of matrix metalloproteinases in vascular disease Vascular Medicine, May 1, 2002; 7(2): 117 - 133. [Abstract] [PDF]
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F. J. Miller Jr, W. J. Sharp, X. Fang, L. W. Oberley, T. D. Oberley, and N. L. Weintraub Oxidative Stress in Human Abdominal Aortic Aneurysms: A Potential Mediator of Aneurysmal Remodeling Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 560 - 565. [Abstract] [Full Text] [PDF]
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K.G. Jones, D.J. Brull, L.C. Brown, M. Sian, R.M. Greenhalgh, S.E. Humphries, and J.T. Powell Interleukin-6 (IL-6) and the Prognosis of Abdominal Aortic Aneurysms Circulation, May 8, 2001; 103(18): 2260 - 2265. [Abstract] [Full Text] [PDF]
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S. Abu-Hayyeh, M. Sian, K. G. Jones, A. Manuel, and J. T. Powell Cadmium Accumulation in Aortas of Smokers Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 863 - 867. [Abstract] [Full Text] [PDF]
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 T. E. Bunton, N. J. Biery, L. Myers, B. Gayraud, F. Ramirez, and H. C. Dietz Phenotypic Alteration of Vascular Smooth Muscle Cells Precedes Elastolysis in a Mouse Model of Marfan Syndrome Circ. Res., January 19, 2001; 88(1): 37 - 43. [Abstract] [Full Text] [PDF]
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 K. Notoya, D. V. Jovanovic, P. Reboul, J. Martel-Pelletier, F. Mineau, and J.-P. Pelletier The Induction of Cell Death in Human Osteoarthritis Chondrocytes by Nitric Oxide Is Related to the Production of Prostaglandin E2 Via the Induction of Cyclooxygenase-2 J. Immunol., September 15, 2000; 165(6): 3402 - 3410. [Abstract] [Full Text] [PDF]
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 Q. Xu, Y.-S. Ji, and J. F. Schmedtje Jr. Sp1 Increases Expression of Cyclooxygenase-2 in Hypoxic Vascular Endothelium. IMPLICATIONS FOR THE MECHANISMS OF AORTIC ANEURYSM AND HEART FAILURE J. Biol. Chem., August 4, 2000; 275(32): 24583 - 24589. [Abstract] [Full Text] [PDF]
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F. J. Miller Jr, W. J. Sharp, X. Fang, L. W. Oberley, T. D. Oberley, and N. L. Weintraub Oxidative Stress in Human Abdominal Aortic Aneurysms: A Potential Mediator of Aneurysmal Remodeling Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 560 - 565. [Abstract] [Full Text] [PDF]
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