(Circulation. 1997;95:205-212.)
© 1997 American Heart Association, Inc.
Articles |
Evidence for Altered Balance Between Matrix Metalloproteinases and Their Inhibitors in Human Aortic Diseases
Harvard Medical School, Brigham and Women's Hospital, Boston, Mass.
Correspondence to Peter Libby, MD, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115. E-mail plibby@bustoff.bwh.harvard.edu.
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Abstract |
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Background Although abdominal aortic aneurysms (AAAs) exhibit increased expression of matrix metalloproteinases (MMPs), the functional balance between MMPs and their tissue inhibitors (TIMPs) remains uncertain. This report compares the proteolytic activity in normal aorta, aorto-occlusive disease (AOD), and AAA by use of a novel in situ zymographic technique.
Methods and Results Infrarenal aortic specimens were obtained from 25 patients undergoing surgery for AOD or AAA and were compared with normal aortic tissue (n=7) obtained from cadavers. Immunohistochemical staining was performed for collagenase (MMP-1), gelatinase A (MMP-2), stromelysin (MMP-3), TIMP-1, and TIMP-2. Net proteolytic activity was determined with in situ zymography whereby aortic sections were incubated on fluorescently labeled substrate. Proteolytic activity was detected under epifluorescent examination. Compared with normal aortic tissue, AOD and AAA tissue demonstrated marked increases in MMP-1 and MMP-3 immunoreactivity, predominantly in the neointima, and modest increases in TIMP-1. MMP-2 was increased in the diseased aortas, and TIMP-2 was abundant in normal, AOD, and AAA samples. Zymography revealed proteolytic activity in AOD and AAA tissues with active digestion of casein and gelatin substrate, particularly on the luminal portion of the specimens. Normal specimens exhibited no lytic activity. Comparison of AOD and AAA specimens revealed no difference in MMP/TIMP immunoreactivity or net proteolytic activity.
Conclusions MMP expression is markedly increased in AOD and AAA samples, and an imbalance between MMPs and their inhibitors results in similar proteolytic activity. The eventual formation of aneurysmal or occlusive lesions appears not to result from an ongoing difference in the proteolytic pattern.
Key Words: aneurysm • atherosclerosis • collagen • metalloproteinases • aorta
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Introduction |
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The origin of AAA formation remains controversial. A relationship exists between atherosclerosis and AAA, although a direct causality remains unproved.1 2 3 4 Immunologic, genetic, and hemodynamic factors may contribute to the pathogenesis of AAA.5 6 7 8 9 Enzymes that weaken the ECM appear pivotal in plaque rupture and SMC migration and may contribute to AAA formation.10 11 12 13 14 15 16 17 Excessive degradation of the ECM may explain why some patients develop infrarenal aortic aneurysmal disease and others develop AOD.7 14 16 17
A specialized family of zinc-containing enzymes known as MMPs can degrade components of the vascular ECM.18 19 MMPs are secreted as inactive precursors by SMCs, inflammatory cells, and fibroblasts.14 In vivo, the zymogen forms of these enzymes require proteolytic cleavage to convert to their active forms.14 Endogenous TIMPs also regulate MMP activity.18 19 20 One member of the MMP family, MMP-3, degrades proteoglycan core proteins, fibronectin, collagen IV and V, laminin, and gelatin and can activate other MMPs.14 Proteoglycans are closely associated with matrix proteins and increase protein resistance to lysis.21 MMP-3 digestion of proteoglycan core proteins can thereby enhance subsequent elastin degradation. TIMP-1 can inhibit MMP-3 activity.20
MMP-1 is activated by MMP-3 or plasmin and contributes to the breakdown of fibrillar collagen.22 23 TIMP-1 also inhibits MMP-1.20 MMP-2 degrades type IV and V collagens, elastin, and gelatin (a breakdown product of collagen). The proteinase inhibitor TIMP-2 selectively limits MMP-2 activity.24
Several investigators have described an increase in elastolytic activity in AAA specimens.10 17 25 26 27 28 29 30 31 32 An imbalance between MMPs and their inhibitors could result in weakening and dilation of the aortic wall by destruction of elastin and collagen and represent a discriminating mechanism of AAA versus AOD development.33 The contribution of proteolysis to these aortic diseases, however, remains controversial. Although studies document increased expression of MMP in AAA tissue, a differential MMP expression in AAA versus AOD states is unresolved. Furthermore, because existing MMP assays require extraction from the in situ environment and, in many cases, post hoc activation, it is unclear whether the assayed MMPs exist as inactive precursors or activated enzymes. Knowledge of the functional balance between activated MMPs and their inhibitors also remains incomplete.
A recently described in situ zymographic technique identifies proteolytic activity in excess of endogenous inhibition.34 The technique uses frozen section specimens, and proteolytic activity is demonstrated by the appearance of dark lytic zones on fluorescently labeled substrates. We examined net proteolytic activity using this novel technique in aortic tissue from patients without atherosclerosis, with AAA, and with AOD without aneurysm. The distribution of certain MMPs and inhibitors in these specimens was determined with immunocytochemical analyses.
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Methods |
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Aortic specimens were obtained from patients undergoing surgery for AOD (n=7) or elective AAA repair (n=18). Excess infrarenal aortic tissue excised from the anterior aortic wall before synthetic graft reconstruction was immediately inspected by the pathologist. A specimen
2x2 cm was released for investigation according to guidelines for the handling of human tissue samples from the Human Research Committee of Brigham and Women's Hospital (Boston, Mass). Normal infrarenal aortic tissue (n=7) was obtained from cadaver specimens supplied by the PDAY tissue bank courtesy of Dr Gray Malcolm (Louisiana State University, New Orleans) and was stored at -80°C. To further assess proteolytic activity in nonatherosclerotic tissue, fresh arterial tissue was obtained from the thoracic aorta and carotid arteries of patients meeting brain death criteria and undergoing heart donation. Serial cryostat sections (6 µm) were cut from tissue imbedded in OCT (Miles) and frozen in 2-methylbutane cooled with liquid nitrogen. Sections were placed onto poly-L-lysine–coated slides and air-dried. Paraffin sections of formalin-fixed specimens were stained with hematoxylin and eosin to assess general morphology and with Verhoeff–van Gieson stain to evaluate the elastin content of the aortic media.
In AAA specimens, the aortic medial wall thickness was measured from the outer border of the necrotic lipid core of the intima to the luminal border of the adventitia. In AOD samples, the formation of a neointima obliterated the internal elastic lamina. In these specimens, neointimal/medial thickness was approximated by measurement of the extent of SMCs, collagen, and elastin between the intimal plaque and adventitia.
Immunocytochemistry
Cryostat sections were fixed in cold acetone (-20°C) and preincubated with 0.3% hydrogen peroxide in Dulbecco's PBS to block endogenous peroxidase activity. The sections were incubated with primary antibodies diluted in 10% horse serum/PBS at room temperature for 60 minutes. After the sections were washed in 2% horse serum/PBS, species-appropriate biotinylated secondary antibodies were applied, followed by avidin-biotin peroxidase complex (Vectastain ABC kit, Vector Labs, Inc). Antibody binding was visualized with 3-amino-9-ethyl-carbazole (Sigma Chemical Co). Sections were counterstained with Gill's hematoxylin (Sigma).
The following primary monoclonal antibodies were used for immunocytochemical analysis: anti-human muscle actin HHF-35 (Enzo Diagnostics); anti-human macrophage HAM-56 (Dako Corp); anti-human leukocyte common antigen LCA (Dako); and anti-human von Willebrand factor (Dako), a constitutively expressed endothelial cell marker.
MMP-1 and MMP-3 immunoreactivity were detected by use of rabbit polyclonal antibodies (M.W. Lark, Merck Research Labs). A monoclonal antibody against TIMP-1 was provided by Oncogene Science; a monoclonal antibody against MMP-2 was obtained from Molecular Oncology; and rabbit polyclonal antiserum against TIMP-2 purified from human melanoma cells was generously provided by Dr William Stetler-Stevensen.
Immunocytochemical data were described qualitatively and semiquantitatively; no staining was recorded as 0; weak, patchy staining as 1; moderate, patchy staining as 2; moderate, diffuse staining as 3; and strong, diffuse staining as 4. The intima, media, and adventitia of each specimen were evaluated in a blinded fashion (ie, the recorder was not aware whether the specimen represented AOD or AAA). Data were reported as mean±SEM. Student's t tests and ANOVA were used for statistical analysis with the aid of the SYSTAT software (Systat, Inc) on a personal computer.
In Situ Zymography
As previously described, 1% agarose melted in 50 mmol/L Tris-HCl, pH 7.4, containing 10 mmol/L calcium chloride and 0.05% Brij 35 was mixed 1:1 with 1 mg/mL casein-resorufin or gelatin-FITC (Boehringer Mannheim) and applied as a film to glass slides.34 Cryostat aortic sections, Tris buffer, and coverslips were applied to the slides, which were incubated at 37°C. Under epifluorescent examination, caseinolytic or gelatinolytic activity was detected as dark-appearing zones lacking fluorescence as a result of digestion of the substrate-fluorescent molecule complexes. Slides with or without the chemical metalloenzyme inhibitors-1,10-phenanthroline (1 mmol/L; Sigma) and EDTA (20 mmol/L) and with or without the serine proteinase inhibitor PMSF (2 mmol/L) were prepared. Casein digestion indicated MMP-3–mediated proteolysis in excess of inhibition by TIMPs; gelatin digestion indicated gelatinase activity (MMP-2 or MMP-9) in excess of TIMPs.
Specimens were examined every 3 days over a 30-day period. Digestion in normal, AOD, and AAA specimens was described qualitatively from serial sections and compared at consistent time intervals of incubation. Frozen (-70°C) specimens demonstrated proteolytic activity several months after acquisition, allowing comparison of stored PDAY control tissue with aortic specimens obtained intraoperatively. In addition to PDAY infrarenal aortic tissue, diseased aortic specimens were compared with fresh arterial specimens obtained from the normal-appearing thoracic aortas and carotid arteries of heart donors.
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Results |
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Demographics
Demographic characteristics of the 25 patients with aortic disease (Table 1
) showed that only age and incidence of peripheral vascular disease differ significantly between patients with AAA versus those with AOD. In patients presenting for AAA repair, the mean size of aneurysm, measured as maximal infrarenal aortic transverse diameter by ultrasound or CT, was 5.4±0.9 cm (range, 5.0 to 7.5 cm). All patients were asymptomatic at the time of presentation for AAA repair. Cadaver specimens were obtained from 7 men whose average age was 27±5 years. Further demographic information was not available for this population.
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Histology
Histological evaluation of aortic specimens revealed fragmentation and depletion of elastin and SMCs in the media of AAA. In AOD tissue, abundant elastin and SMCs were present in the media (Fig 1). A thickened media was noted in AOD but not in AAA specimens (Table 2). Intimal thickening characterizes both AAA and AOD. In AAA, this thickening results primarily from necrotic, lipid-laden plaque formation. In AOD, the neointima includes marked SMC accumulation and atherosclerotic debris. Control aortic specimens contained modest fatty streak formation without atherosclerotic plaque accumulation.
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-actin (anti-human
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In accordance with prior observations, stains for macrophages and leukocytes revealed prominent transmural inflammatory infiltrates, particularly in the media and adventitia of the AOD and AAA aortas. Von Willebrand factor stains also revealed significant neovascularization in the diseased aortas. No vessels were apparent in the intima and media of the normal aortas.
MMPs and TIMPs
Control immunocytochemical staining was performed in tissue specimens by use of mouse IgG or preimmune serum to evaluate background nonspecific staining. Fig 2 compares representative MMP and TIMP staining in AOD and AAA specimens with normal aortas. Normal aortic tissue revealed little MMP immunoreactivity, although moderate amounts of inhibitors were present. Within the AOD and AAA aortic specimens, MMP immunoreactivity was evident in the intima, media, and adventitia. SMCs in the neointima and media of the diseased aortas stained positive for MMP, as did macrophages and leukocytes in areas of inflammation. Many of the AAA specimens exhibited few remaining SMCs and a vestigial tunica media, although they contained immunoreactive MMP in plaque, fibrous tissue, and regions of angiogenesis and inflammation. Diseased aortas exhibited abundant, diffuse staining for both TIMP-1 and TIMP-2 (Fig 2). SMCs, macrophages, and leukocytes stained positive for TIMP in regions of intimal plaque, residual media, and adventitia. Within the media, the increases in MMPs in diseased aortas colocalized to areas of increased TIMPs.
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Semiquantitative analysis of diseased aortas demonstrated substantially greater staining for MMP-1 and MMP-3 than in normal specimens (Table 3). There was a corresponding increase in the MMP-1 and MMP-3 inhibitor TIMP-1 in AOD and AAA (Table 3). These increases are apparent in the intima, media, and adventitia. There was no difference in MMP-1, MMP-3, or TIMP-1 immunoreactivity between AOD and AAA specimens when the separate arterial wall layers were compared by t test or when the intima, media, and adventitia scores were compared by ANOVA. Increases in immunoreactivity in diseased aortas versus normal also were noted for MMP-2 and were noted predominantly in the intima (Table 4). Staining for the MMP-2 inhibitor TIMP-2 was markedly positive in normal, AOD, and AAA specimens (Table 4). There was no difference in MMP-2 or TIMP-2 staining between AOD and AAA specimens by t test or ANOVA.
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MMP-2 semiquantitative immunoreactivity scores were slightly higher in the intima and adventitia of AAA than in AOD specimens and were slightly decreased in the media of AAA. Comparison of the intima, media, and adventitia scores together by ANOVA showed no difference between AOD and AAA (Table 4
). To demonstrate a significant difference by t test in the MMP-2 or TIMP-2 scores for the intima or adventitia between AOD and AAA (effect size, 0.4; SD of the outcome variable, 0.8), 84 aortas per group would be required to achieve a two-tailed value of P=.05 and P=.10.
In Situ Zymography
Of the normal specimens studied, including PDAY infrarenal aortic tissue and fresh thoracic aortic and carotid artery tissue, none exhibited digestion of casein or gelatin (Fig 3). Both AOD and AAA specimens resulted in similar patterns of digestion of the substrates (Fig 3). In diseased aortas, the metalloenzyme inhibitors phenanthroline and EDTA markedly reduced caseinolytic activity; however, the serine proteinase inhibitor PMSF does not block caseinolytic activity in sections of atheroma (data not shown here but previously reported by Galis et al34 ).
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Both caseinolytic and gelatinolytic activity were most apparent on the luminal aspect of the diseased aortas and in the lipid core region of the plaque. Digestion was noted less commonly in the adventitia and rarely in the media. This method does not permit quantitative analysis, although qualitative analysis confirms caseinolytic and gelatinolytic activity in both AOD and AAA specimens and does not demonstrate an apparent difference between AOD and AAA specimens (Fig 3).
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Discussion |
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Risk factors for patients with AOD and AAA are similar, although AAA tends to develop at a later age, suggesting a delayed manifestation of the atherosclerotic process.1 2 3 4 Atherosclerosis is common in the infrarenal aorta, and a compensatory dilation occurs in response to atheroma accumulation.35 Hemodynamic factors coupled with degeneration of the media could result in pathological aortic dilation.35 36 It remains unclear, however, why some patients with atherosclerosis develop infrarenal AOD while others develop AAA.
Proteinases, specifically MMPs, contribute to the atherosclerotic process through the degradation of the ECM, thereby facilitating SMC migration, angiogenesis, and plaque formation. Additionally, because elastin in the aortic media of patients with AAA is markedly depleted, several investigators have proposed an imbalance in proteolytic/antiproteolytic activity as an etiologic factor.33 37 Proteinase production by aortic wall mesenchymal cells, the pancreas, and leukocytes is increased in patients with AAA.10 13 15 17 25 27 28 29 30 38 Several of these proteinases have been isolated by use of N-succinyl-(ala)3-P-nitroanilide substrate, are inhibited by PMSF, and are classified as serine proteases.33 39 Other proteinases, which appear critical in ECM degradation, contain zinc, are inhibited by EDTA and phenanthroline, and are classified as MMPs.17 18
Despite the number of recent reports indicating increased MMP expression in AAA, the pathogenic significance remains uncertain.28 29 30 McMillan et al28 found elevated levels of MMP-9 mRNA in AAA tissue compared with controls but no difference between AAA and AOD tissue. Compared with normal aortic tissue, Thompson et al30 noted a 6-fold increase in MMP-9 levels by ELISA in AOD and a 10-fold increase in AAA tissue. Interestingly, TIMP-1 was also markedly elevated in AAA but not in AOD specimens.30 Preparation of aortic extracts designed to separate MMPs from their substrate and natural inhibitors is difficult and often requires artificial activation of the MMP or blocking of the inhibitor.14 MMPs are secreted as inactive precursors; however, the common method of analysis of extracted MMPs, on SDS-containing substrate electrophoretograms, activates gelatinases.14 40 Heretofore, most studies of MMP expression in aortic disease have not completely assessed the in situ state, eg, activated versus precursor forms, intracellular versus extracellular location, or the presence or absence of endogenous inhibitors.
The tissue inhibitors are ubiquitous in the extracellular aortic milieu, and unstimulated SMCs contain high levels of TIMP-1 and TIMP-2 mRNA and protein.12 Brophy et al37 demonstrated an increase in soluble TIMP in AAA and a decrease in the matrix-associated TIMP. McMillan et al28 found no difference in TIMP-1 mRNA levels between AAA, AOD, and normal aortic tissue. An in situ analysis of the MMP:TIMP balance has not been reported.
This study evaluates alterations in the functional balance between MMP and TIMP in AAA and AOD tissue compared with control cadaver aortic and fresh arterial specimens. In situ zymography allows demonstration of net caseinolytic or gelatinolytic activity in cryostat sections of arteries.34 Tissue preparation involving extraction and activation of latent proteinases or blocking of endogenous inhibitors is not required. Proteolytic activity remains demonstrable in frozen tissue samples many months after harvest. Because actual net proteinolytic activity is assessed, data interpretation is not confounded by assumptions regarding latency or in situ inhibition. The addition of serine or MMP proteinase inhibitors provides information regarding the predominant proteinase responsible for digestion. MMP-3 activity in excess of endogenous inhibitors (eg, TIMP-1) in an aortic specimen produces dark lytic zones in the casein substrate seen under fluorescent microscopy. Lysis of the gelatin substrate indicates net excess of activated gelatinases (MMP-2, MMP-9, or to a lesser extent MMP-1) over the inhibitor TIMP-1, TIMP-2, or TIMP-3. These substrates do not evaluate elastin degradation, however.
Previous work with in situ zymography in normal rabbit iliac arteries demonstrated a lack of casein or gelatin digestion, although balloon-injured iliac arteries from cholesterol-fed animals revealed prompt substrate digestion.34 Human atherosclerotic arteries obtained from endarterectomy or transplant donor specimens also reveal casein and gelatin digestion, which is reduced in the presence of MMP inhibitors.41 Human arterial tissue without atherosclerotic change shows no substrate digestion.41
In this study, in situ zymography demonstrated no digestion in normal cadaveric aorta or fresh arterial tissue, consistent with findings of abundant TIMP and minimal MMP immunoreactivity. In both AAA and AOD tissue, excess proteolytic activity (caseinolytic and gelatinolytic) was seen with maximal digestion in the luminal aspect of the tissue and large amounts of digestion in the neointima. Digestion was markedly reduced by phenanthroline and EDTA, not by PMSF, consistent with metalloenzyme activity. Minimal digestion was noted in the aortic media caused perhaps by substrate competition between the casein or gelatin gels and the native aortic media. The in situ zymographic results suggested that the large increases in MMP immunoreactivity in the diseased aortas overwhelm the more modest increases in TIMP. The in situ technique confirms excess MMP activity in the diseased aortas, with a similar pattern of proteolysis for both AAA and AOD.
Limitations of the in situ zymographic technique include an inability to assess or control specimen variability in proteoglycan concentration, inactive mutant enzymes, or mineral imbalances that may affect metalloenzyme activity. In vitro assays allow control of these variables. Furthermore, casein and gelatin, although useful substrates for proteolysis, do not possess all the characteristics of the aortic ECM and do not evaluate elastin degradation.
As demonstrated, AAA patients have decreased aortic media wall thickness compared with AOD patients and depleted SMC and elastin content despite a proteolytic pattern similar to that in AOD patients. Immunocytochemical analysis demonstrates small amounts of MMP protein in normal specimens and increased levels of MMP-1, MMP-2, and MMP-3 in AAA and AOD tissue, with no difference between AAA and AOD specimens. It is possible that matrix-degrading enzymes (eg, elastases) or inhibitors not studied here or not yet identified may be present preferentially in AAA specimens. MMPs may contribute to the atherosclerotic process by degrading the ECM to allow SMC migration, angiogenesis, and compensatory arterial enlargement; however, our results call into question the primary role for MMP imbalance in formation of aneurysms versus occlusive lesions.
In this study, the AAA patients were older than the AOD patients. Because we obtained AAA tissue only from patients requiring surgical intervention, our results cannot exclude the possibility of higher levels of net proteolytic activity at an earlier stage of aneurysm formation. Alternative mechanisms for aortic aneurysm formation include participation of proteolytic activities not assessed here, altered production of matrix elements, increased susceptibility of the matrix to degradation, or a reflection of an advanced stage of the atherosclerotic process.
Etiologic factors other than atherosclerosis are presumably involved in AAA formation because certain patients develop generalized arteriomegaly at relatively young ages before the onset of atherosclerotic disease.5 Analysis of the aortic media in these patients demonstrates relative deficiencies of elastin and increases in collagen.42 Furthermore, patients with AAA have an increased prevalence of peripheral arterial aneurysms and their family members have an increased risk of AAA formation.43 Although aortic elastin is thought to accrue exclusively during the early stages of life, reports demonstrate increased SMC production of procollagen mRNA in adult AAA specimens.44 45 46 Resultant increased collagen-to-elastin ratios could be responsible for the aortic media wall weakness and infrarenal aortic dilation.
SMCs of the infrarenal aorta grow poorly in tissue culture and appear to have a different phenotype than SMCs from the thoracic aorta, which have greater replicative potential.13 Because both AOD and AAA specimens exhibit net proteolytic activity, patients who develop AAA may be more susceptible to elastin degradation or less capable of maintaining reparative processes.
In summary, our results demonstrate SMC and elastin depletion in the aortic media of patients with AAA in contrast to the fibrotic, proliferative changes seen in patients with AOD. Despite these disparate histological appearances, both AAA and AOD aortic specimens exhibit similar increases in MMP immunoreactivity compared with control cadaver specimens. Furthermore, a novel in situ zymographic technique that directly examines net proteolytic activity reveals similar digestion in both AAA and AOD tissue. We conclude that an imbalance exists between MMPs and their inhibitors in aortic disease states; however, the eventual formation of aneurysms or stenotic lesions may depend on other as-yet-undefined factors than the proteinases studied.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grant HL-48743 from the NHLBI. We are grateful to Gray Malcolm, MD, Louisiana State University, New Orleans, for generously providing cadaver aortic specimens from the PDAY tissue bank; William Stetler-Stevensen, MD, PhD, NIH, Bethesda, Md, for providing antibodies; and Zorina S. Galis, PhD, for assistance with in situ zymography.
Received April 24, 1996; revision received August 15, 1996; accepted October 7, 1996.
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