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From the Cerebrovascular Research Laboratory, Section of Cerebrovascular
Surgery, Department of Neurosurgery, The Cleveland Clinic Foundation (Ohio).
Correspondence to Douglas Chyatte, MD, Section of Cerebrovascular Surgery, Department of Neurosurgery–S80, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail chyattd{at}cesmtp.ccf.org
Methods—Serum samples were collected from surgical patients with
intracranial aneurysms. The following series of experiments was
designed to further characterize and identify the predominant serum
gelatinase found in the subgroup of patients with increased gelatinase
activity. Gelatin zymography was performed on native serum samples and
compared with serum that had been pretreated with a known
metalloproteinase activator (4-aminophenylmercuric acetate
[APMA]). Gelatin zymography was repeated in the presence of a matrix
metalloproteinase (MMP) inhibitor (EDTA) and a serine
proteinase inhibitor (phenylmethylsulfonyl fluoride
[PMSF]). Final identification was made by Western blotting with the
use of monoclonal antibodies to MMP-2 and MMP-9.
Results—A consistent gelatinolytic
band (72 kDa) was identified in all serum samples (n=60). Pretreatment
of the serum by APMA (n=60) lowered the molecular weight of the band to
66 kDa. The band was inhibited by EDTA (n=10) but not PMSF (n=10), thus
characterizing the circulating 72-kDa gelatinase as an inactive
pro-MMP. Western blotting (n=20) identified the 72-kDa band as
MMP-2.
Conclusions—These findings confirm that the increased
gelatinolytic activity observed in vitro in a
subset of cerebral aneurysm patients is due to pro-MMP-2.
Previous work by this laboratory has found a 3-fold increase in a
72-kDa serum gelatinase in a subgroup of aneurysm patients. In
that study, aneurysm patients (52% ruptured, 48% unruptured)
were compared with surgical patients known to be free of cerebral
aneurysms. One half of the aneurysm patients had a
3-fold increase in serum gelatinase activity as measured by
quantitative gelatin zymography compared with the controls. This
increased activity was irrespective of their hemorrhage
status.7 Vascular extracellular matrix (ECM)
remodeling is known to be orchestrated and regulated by a complex
network of proteases and protease
inhibitors.8 9 10 Molecular markers of
matrix remodeling have been found in both cerebral and aortic
aneurysm patients.7 11 The purpose of the
present study was to further characterize and identify this
circulating gelatinase.
The families of matrix metalloproteinases (MMPs) and serine proteinases
both participate in ECM remodeling, and each contains proteases capable
of digesting gelatin.12 The MMPs are a homologous
group of zinc- and calcium-dependent matrix proteases that are secreted
as zymogens.13 Two members of this family, MMP-2
and MMP-9, are known respectively as gelatinase A (72 kDa) and
gelatinase B (92 kDa) because of their strong affinity to that
substrate in vitro.14 Of the serine proteases
known to degrade gelatin, plasmin (75 kDa) has the closest molecular
weight to the gelatinase in question.
Characterization of this gelatinase as an MMP or a serine protease was
accomplished by studying its behavior in the presence of known protease
inhibitors. Ethylenediaminetetraacetic acid (EDTA), a
divalent cation chelator, is known to inhibit activation of MMPs, while
phenylmethylsulfonyl fluoride (PMSF) is a known serine protease
inhibitor. 4-Aminophenylmercuric acetate (APMA), a known
MMP activator, was used to determine whether this
gelatinase was an inactive zymogen or active protease. Characterization
of the gelatinase in this way allowed for presumptive identification as
an MMP. Final identification was confirmed by Western blotting with the
use of monoclonal antibodies to MMP-2 and MMP-9.
Sample Collection
Gelatin Zymography
Serum samples were prepared as follows for activation with APMA. First
25 µL of 5 mmol/L APMA was added to 100 µL of undiluted serum
and incubated in a 37°C water bath for 90 minutes. The reaction was
stopped with 10 mmol/L EDTA, and the samples were dialyzed for 18
hours to remove the APMA. The samples were then loaded on gels, and the
zymography protocol was followed as above.
Western Blotting
In 10 patients showing the greatest lysis of gelatin at 72 kDa, EDTA
was added to the zymographic developing buffer and in all cases
completely inhibited the 72-kDa band of gelatin lysis. PMSF, a known
inhibitor of serine proteases, did not inhibit gelatin
lysis at the 72-kDa mark when added to the zymographic developing
buffer in these patients.
Western blotting in the above 20 patients with a monoclonal antibody
against MMP-2 revealed a consistent band at the appropriate
molecular weight that corresponded to the commercial MMP-2 standard
(Figure 2
Although increased levels of MMP-2 are known to be a marker of invasive
potential and metastasis in certain
neoplasms,21 22 23 24 the increased circulating levels
of pro-MMP-2 in some cerebral aneurysm patients may be an
epiphenomenon. MMP-2 is known to be secreted by a variety of different
cell types, including fibroblasts, macrophages, leukocytes,
smooth muscle cells, and endothelial
cells.25 26 27 28 29 It is a known participant in normal
and pathological ECM remodeling, angiogenesis, and cell
migration.12 30 31 It is conceivable that some
condition(s) either directly or indirectly related to aneurysm
formation may influence circulating pro-MMP-2 levels by acting on sites
distant from the cerebral aneurysm. Alternatively, it is
possible that pro-MMP-2 may be shed from the region of the cerebral
aneurysm representing a circulatory marker of
molecular events occurring with the aneurysm wall.
We next considered the possibility that MMP-2 was playing an
active role in the matrix degradation that either initiated or
propagated the formation of intracranial aneurysms. Although
the precise method of pro-MMP-2 activation in vivo has not been
characterized, recent publications have identified a unique multistep
activation pathway that involves members of both ECM-degrading
families. In both pathways, activation occurs on the cell surface,
targeting activation of pro-MMP-2 to specific anatomic sites. The
transmembrane MMPs (MT1-MMP and MT2-MMP) have been shown to
activate pro-MMP-2, in some cases forming a 64-kDa
intermediate.32 33 Recently, the plasmin
activator–plasmin system was implicated in the second stage of
MMP-2 activation to the final active 62-kDa
form.34 Other studies show the urokinase-plasmin
system playing a larger role in the control of gelatinase
activity.35 This is of interest since we recently
localized both plasmin and MT1-MMP in cerebral aneurysm tissue,
raising the possibility of localized activation of MMP-2 within the
aneurysm.36
In conclusion, increased circulating levels of pro-MMP-2 occur in a
subset of cerebral aneurysm patients. The relationship of this
observation to the mechanisms that result in aneurysm formation
and growth remains to be defined.
Received January 29, 1998;
revision received April 24, 1998;
accepted May 20, 1998.
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Original Contributions
Identification of a Serum Gelatinase Associated With the Occurrence of Cerebral Aneurysms as Pro-Matrix Metalloproteinase-2
Abstract
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Background and
Purpose—Subarachnoid hemorrhage from intracranial
aneurysm rupture produces a severe form of stroke.
Extracellular matrix remodeling is associated with cerebral
aneurysms and may play a role in the formation or rupture of
these lesions. We previously reported a 3-fold increase in a 72-kDa
serum gelatinase in a subgroup of aneurysm patients. The
purpose of the present study was to further characterize and
identify this gelatinase.
Key Words: cerebral aneurysm • gelatinases • metalloproteinases
Introduction
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Cerebral
aneurysms usually remain asymptomatic until rupture
occurs. Despite modern therapy, aneurysmal subarachnoid
hemorrhage remains one of the most severe forms of
cerebrovascular disease, with a mortality approaching
50%.1 2 3 4 5 6 Understanding the biology of cerebral
aneurysms may lead to new therapeutic strategies for these
extremely ill patients.
Materials and Methods
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Patients
Patients undergoing surgical treatment of cerebral
aneurysm as documented by cerebral angiography were included in
the study. Informed consent was obtained in accordance to the protocol
approved by the Institutional Review Board before collection of any
samples. The sex, age, and presence or absence of subarachnoid
hemorrhage was recorded for each patient at the time of
sample collection.
Blood was collected immediately before surgery by
venipuncture in an evacuated tube. After we allowed
for clot formation, the blood was centrifuged at 2000 rpm for
10 minutes, aliquoted, and stored at -70°C.
Gelatinase substrate gel electrophoresis was performed with the
use of precast gels (10% polyacrylamide containing 0.1%
gelatin, Novex). Samples were prepared by dilution (1:200) into
a loading buffer consisting of 0.4 mol/L Tris, pH 6.8, 5% SDS, 20%
glycerol, 0.03% bromophenol blue, and 20 µL of serum loaded per
lane. After electrophoresis at 125 V, the gels were incubated in
renaturing solution (2.5% Triton-X-100) for 30 minutes at room
temperature and then for 72 hours at 37°C in a developing buffer
containing 50 mmol/L Tris, pH 7.5, 200 mmol/L NaCl, 4
mmol/L CaCl2, and 0.02% Brij-35. When appropriate,
the developing buffer contained 20 mmol/L EDTA, a known
inhibitor of MMPs, or l mmol/L PMSF, a known
inhibitor of serine proteases. The gels were then stained
with Coomassie blue, and regions without staining were indicative of
gelatin lysis.
Serum was diluted 1:100 with ultrapure double-distilled water
(18-
resistance), mixed 1:4 with loading/reducing buffer, denatured
at 95°C for 5 minutes, and flash spun at 7000 rpm. A total volume of
30 µL was loaded per lane. The proteins separated electrophoretically
on a 10% Tris-HCl polyacrylamide gel for 45 minutes at 200
constant voltage. Commercially obtained protein standards for MMP-2 and
MMP-9 (Chemicon) were loaded on every gel. The gel was transferred to a
supported nitrocellulose membrane by overnight electrophoresis (190 mA
at 4°C). The membrane was blotted according to ECL Western blotting
protocol (Amersham RPN2106) with MMP-2 and MMP-9 monoclonal antibodies
(Calbiochem) diluted according to manufacturer's specifications.
Results
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Serum samples were collected from 60 aneurysm patients.
The mean age of the group was 54 years (range, 25 to 79 years), and 40
patients (67%) were women. Thirty-five were treated for unruptured
aneurysms (58%), and 25 patients presented with SAH
(42%). Gelatin zymography of the native serum revealed a
consistent band of gelatin lysis at 72 kDa in all 60 patients.
Ten of the above patients were randomly selected and underwent repeated
zymography after treatment of the serum with APMA. In these patients,
the previously noted band of gelatinase activity at 72 kDa was replaced
by a band at 66 kDa (Figure 1
).
View larger version (22K):
[in a new window]
Figure 1. Serum gelatin zymography. N indicates native
serum; A, serum activated with APMA. Native serum forms a band
at 72 kDa, while activated serum is seen at 66 kDa. ). The Western blots were
repeated in these patients with a monoclonal antibody against MMP-9,
and no reactivity was observed except in the protein standard. These
data definitively identified the gelatinase in question as
pro-MMP-2.
View larger version (42K):
[in a new window]
Figure 2. Western blot of serum from aneurysm
patients probed with monoclonal antibody to MMP-2. A indicates
aneurysm patient; STD, molecular weight standard; and PSC,
pooled serum control.
Discussion
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Circulating levels of pro-MMP-2 are increased in some patients
with cerebral aneurysms. Increased serum-, plasma-, and
tissue-bound MMP-2 and other MMPs are associated with the
occurrence of vascular diseases such as aortic aneurysms and
atherosclerosis.7 15 16 17 18 19 Under
normal circumstances, the transcription, secretion, and activation of
MMP-2, as well as other MMPs, are tightly
regulated.13 20 The mechanisms that alter
circulatory pro-MMP-2 levels and the nature of their relationship to
cerebral aneurysm formation in some patients are unknown.
Acknowledgments
This study was supported by the National Institutes of Health
(grant 1R01 HL 57103–01A1) and the Northeastern Ohio Affiliate of the
American Heart Association (grant 96–102-SG).
References
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
1.
Chyatte D, Fode NC, Sundt TM Jr. Early versus late
intracranial aneurysm surgery in subarachnoid
hemorrhage. J Neurosurg. 1988;69:326–331.[Medline]
[Order article via Infotrieve]
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