Published online before print December 23, 2002, doi: 10.1161/01.CIR.0000044915.37074.5C
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(Circulation. 2003;107:333.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Increased Medial Degradation With Pseudo-Aneurysm Formation in Apolipoprotein E–Knockout Mice Deficient in Tissue Inhibitor of Metalloproteinases-1
From the Division of Molecular Medicine (V.L., J.D.), Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, and the Division of Nutritional Sciences, Cornell University (P.D.S.), Ithaca, NY.
Correspondence to Jeanine D’Armiento, Columbia University, Department of Medicine, P&S 8-401, 630 W 168th St, New York, NY 10032. E-mail jmd12{at}columbia.edu
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Abstract |
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Background— The tissue inhibitor of metalloproteinases-1 (TIMP-1) is expressed in atherosclerotic lesions, where it may play a critical role in regulating the activity of matrix metalloproteinases (MMPs). Several MMPs are overexpressed in the atherosclerotic plaque, and they are believed to contribute to the expansion and rupture of the lesion.
Methods and Results— The Timp-1–knockout mouse model (Timp-1-/-) was crossed into the apolipoprotein E–knockout (apoE0) background. A study population of male apoE0 mice, half of them deficient in TIMP-1, was fed an atherogenic diet. After 10 weeks of the diet, the mean lesion sizes of the two groups of animals were not significantly different, and the average content of fibrillar collagen and macrophages in the lesions was similar. There was no sign of plaque hemorrhage, even after 22 weeks of high-fat diet, indicating that deficiency in TIMP-1 does not predispose to luminal rupture. However the atherosclerotic lesions of the Timp-1-/0 mice developed more aortic medial ruptures, in which all elastic lamellae of the media were degraded and infiltrated with macrophages, forming pseudo-microaneurysms. After 10 weeks of high-fat diet, the Timp-1-/0/apoE0 mice averaged 1.9±1.2 medial ruptures in the proximal aorta, compared with 0.5±0.7 for the apoE0 controls (P<0.003). At the site of degradation, in situ zymography revealed that the gelatinolytic activity, mainly associated with macrophages, could be abolished by the addition of MMP inhibitors.
Conclusions— These data strongly suggest that TIMP-1 plays a key role in preventing medial degradation associated with atherosclerosis through its ability to inhibit the MMPs that are involved in the disruption of the media.
Key Words: mouse • metalloproteinases • atherosclerosis
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Introduction |
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The initiation and progression of atherosclerosis, from the early fatty streaks to the advanced lesions, involve major changes of the neointimal extracellular matrix.1 Two complications of atherosclerosis, plaque rupture and aneurysm formation, are believed to be associated with an excess of proteolytic activity in the lesions.1 Mature atherosclerotic lesions are characterized by the presence of a fibrous cap containing elastic and collagen fibers.2 The disruption of this fibrous cap and the subsequent release of thrombogenic molecules into the circulating blood often result in lethal myocardial infarction.3 Arterial aneurysm development is characterized by the degradation of the proteins forming the extracellular matrix of the media with subsequent dilatation of the arterial wall.4
Endopeptidases belonging to the matrix metalloproteinase (MMP) family5 are believed to contribute significantly to the degradation and remodeling of the plaque extracellular matrix.1 These MMPs, which are not expressed in normal vessels, include interstitial collagenases (MMP-1, -8, -13, and -14) and elastinolytic enzymes (MMP-7, -9, and -12).6–9 They are secreted in latent proforms, requiring the processing of their N-terminal propeptide to be active.5 In vivo, MMPs are inhibited by the tissue inhibitors of metalloproteinases (TIMP). Four human forms of TIMPs, TIMP-1 to -4, have been identified,10 and TIMP-1, -2 and -3 are overexpressed in the atherosclerotic lesions.6,11 TIMP-1 is a 28-kDa glycoprotein with a high affinity for all active MMPs except MMP-2 and MMP-14.10 TIMP-1 also binds to the proform of gelatinase B (MMP-9), slowing its activation.10 Previous studies have suggested that TIMP-1 might play an important role in the development of atherosclerotic lesions12 and in vessel wall degeneration.13 To study the role of TIMP-1 in atherosclerosis, we crossed the Timp-1–knockout mouse into the atherosclerosis-susceptible apoE-knockout background.14,15 The hypercholesterolemic apoE0 mice develop lesions of atherosclerosis that are similar to human lesions but do not rupture.16,17
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Methods |
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Experimental Animals
ApoE0 mice in the C57BL/6 genetic background were obtained from the Jackson Laboratory (Bar Harbor, Me). The generation of the Timp-1-/- mice was previously described.18 Timp-1-/- mice in the C57BL/6 background were used for crossbreeding with apoE0 mice. The animals were genotyped by Southern blot analysis with the TIMP-1 cDNA as a probe.18 Four-week-old mice used in the study population were fed an atherogenic Western-type diet (20% protein, 50% carbohydrate, 21% fat, 0.21% cholesterol; Research Diets) for 10 to 22 weeks and then were euthanized for analysis.
Northern Blot Analysis
Total RNA from peritoneal macrophages was prepared as described previously,19 and Northern blot analysis was performed with the TIMP-1 cDNA as a probe.
Lipid Analysis
Total plasma cholesterol levels from fasted mice were determined by a 4-aminoantipyrine–based enzymatic assay (Wako Bioproducts).
Quantification of Atherosclerosis and Medial Degradation
Mice were euthanized with CO2; the right jugular was nicked and the heart was pressure-perfused at 80 mm Hg via left ventricular puncture, first with PBS and then with 10% neutral buffered formalin for 5 minutes to fix the aorta. A length of 750 µm of the paraffin-embedded proximal aorta was cross-sectioned serially in 10-µm increments. Lesions from every sixth section, for a total of 8 sections, were stained with hematoxylin and eosin (H&E) and quantitated by video microscopy with the Image Pro 3.0 software (Media Cybernetics). An average lesion size was determined for each mouse.20 The total area of the aorta, delimited by the external elastic lamina, was also measured with the same software. The same sections were examined by light microscopy to quantify the degradation of the media, and sites in which the media was completely disrupted, forming pseudo-microaneurysms, were numbered. Degradation of all elastic layers at the medial rupture site was ascertained by examination of adjacent Elastica van Gieson (EVG)–stained sections.
Histological Analysis
In addition to the sections used for quantifications, animals that were fed a high-fat diet for 22 weeks were euthanized for histological analysis of advanced lesions of atherosclerosis. The formalin-perfused aortas were embedded in paraffin. Transversal sections (5 µm) of the aortic root and longitudinal sections of the thoracic and abdominal aortas were stained with H&E, Masson’s trichrome, and EVG as described.21
Immunohistochemistry
Immunohistochemical detections of aortic smooth muscle cells and macrophages were performed with the avidin-biotin-horseradish peroxidase method (Mouse to Mouse kit, Zymed). Macrophages were detected with a rat antimouse Mac-3 monoclonal antibody (Pharmingen) and smooth muscle 
-actin with a mouse monoclonal antibody (Zymed). The activity of the peroxidase was revealed by diaminobenzidine, yielding a brown deposit. Sections were counterstained with methyl green.
Quantification of Lesion Collagen and Macrophage Contents
For each proximal aorta, 4 serial sections 60 µm apart from each other were stained with Masson’s trichrome for collagens. For macrophage quantification, sections were stained with the Mac-3 monoclonal antibody. The stained collagen and macrophages were quantified with video microscopy and Image Pro 3.0 software.
In Situ Zymography
In situ zymography was performed to localize the gelatinolytic activity in the tissue.22 Cryostat sections of 10 µm were overlaid with the assay solution (50 mmol/L Tris-HCl, 5 mmol/L CaCl2, 5 µmol/L ZnCl2, pH 7.5) containing low melting point agarose (0.5% final; BioWhittaker) and 50 µg/mL of quenched FITC-labeled DQ gelatin (Molecular Probes). Sections were incubated at 37°C for 18 hours and examined. MMP inhibitors, 10-mmol/L EDTA, or recombinant bovine TIMP-1 (75 ng/section; Calbiochem), were added to the assay solution as controls.
Statistical Analysis
Unless otherwise specified, analysis was performed by the 2-tailed unpaired Student’s t test, with P<0.05 considered significant.
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Results |
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The study population of apoE0 mice deficient in TIMP-1 was obtained by first crossing a Timp-1-/- female, in the C57BL/6 background, with an apoE0 male (Figure 1). After two generations, a Timp-1-/0/apoE0 male was selected and crossed with apoE0 females. Their progeny were interbred to give a study population of apoE0 males of which
50% were Timp-1 knockout (Figure 1). Only males were used in this study because the gene for TIMP-1 is linked to the X chromosome. The mice were screened by Southern blot before being placed on the Western diet (Figure 1b). Macrophages from Timp-1-/0/apoE0 mice did not express TIMP-1 (Figure 1c).
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The study population was fed an atherogenic, high-fat diet for 10 or 22 weeks. The total plasma cholesterol levels were similar between the Timp-1-/0/apoE0 (1419±495 mg/dL; n=17) and the apoE0 controls (1457±731 mg/dL; n=21). After 10 weeks of the diet, the average lesion size in the two groups of animals was not significantly different (127 749±54 546 µm2 for the Timp-1-/0/apoE0, n=14; 134 978±68 210 µm2 for the apoE0 controls, n=14, Figure 2).
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A qualitative examination of the plaques for cellular and matrix composition was performed, and no significant difference between the two groups of mice was observed. The average macrophage content of the animals was determined: The number of Mac-3–positive cells was not changed in the Timp-1-/0/apoE0 animals (30.8±12.6% of the lesion, n=10) compared with the controls (29.6±4.6%, n=10; P=0.78). The integrity of the matrix in the lesions was further investigated by quantification of the average collagen content of the plaque. The Timp-1-/0/apoE0 mice (n=5) had an average collagen content of 20.4±13.2% of the plaque area, which was not significantly different from the controls (27.7±13.3%, n=5, Figure 2). Histological examination of very advanced lesions from mice that were fed the high-fat diet for 22 weeks (Timp-1-/0/apoE0, n=4; apoE0, n=4) did not reveal any evidence of plaque rupture.
However, after 10 weeks of the diet, a majority of the Timp-1–knockout mice exhibited at least one medial rupture in the proximal aorta, characterized by the complete degradation of the media (Table). These medial degradations were much less frequent in the apoE0 controls (P=0.0052, Fisher’s exact 2-tail test; Table). Figure 3 shows a comparison of aortic sections from a control apoE0 (Figure 3a) and a Timp-1-/0/apoE0 mouse (Figure 3b) after EVG staining. Two medial ruptures can be seen in the Timp-1-/0 mouse section (Figure 3b). Another illustration of medial degeneration in a Timp-1-/0/apoE0 mouse is presented in Figure 3c, demonstrating the destruction of the media and its infiltration by cells from the atherosclerotic lesion.
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1 Medial Rupture
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The number of medial ruptures for each animal was significantly higher in the Timp-1-/0/apoE0 animals (Figure 2, average of 1.9±1.2, n=14) compared with the controls (average of 0.5±0.7 rupture per animal, n=15, P<0.003). The increased medial degradation in the Timp-1-/0/apoE0 animals was not associated with an aneurysmal dilatation of the aortic vessel: The average total area of the aorta (delimited by the external elastic lamina) was not significantly different between the Timp-1-/0/apoE0 (821 499±147 680 µm2, n=10) and the apoE0 controls (937 777±221 348 µm2, n=10; P=0.18).
The observed medial ruptures were characterized by an infiltration of Mac-3–positive macrophages, migrating in an intimal-to-adventitial gradient (Figure 4, arrow), forming pseudo-microaneurysms.23 The site of disruption is also characterized by a decrease in -actin staining due to the diminished number of smooth muscle cells (Figure 4). In situ detection of gelatinolysis with fluorescent peptides (Figure 5) demonstrated that proteolytic activity is mainly detected at the level of the macrophages invading the media at the site of rupture (Figure 5a). This activity was almost completely suppressed by the addition to the section of 10 mmol/L EDTA (data not shown) or recombinant TIMP-1 (75 ng; Figure 5C), indicating that the gelatinolytic activity at the site of medial degradation is very likely attributed to MMPs.
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Discussion |
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The present study demonstrates that deficiency of TIMP-1 significantly increases the medial degradation associated with atherosclerotic lesions in apoE0 mice. The Timp-1–knockout animals presented a higher number of ruptures in the aortic media, in which all elastic laminae were digested and infiltrated with macrophages, forming pseudo-microaneurysms. Because the gelatinolytic activity at the site of medial disruption could be inhibited by EDTA or TIMP-1, it is highly likely that proteases found in the degraded media include MMPs.
Previous correlative studies have demonstrated the expression of MMPs during medial degeneration. For instance, it has been hypothesized that overexpression of gelatinase A (MMP-2) by vascular smooth muscle cells may be responsible for the degradation of the elastin fibers in the early stages of aneurysm development.24 In human abdominal aortic aneurysms, gelatinase B (MMP-9) and metalloelastase (MMP-12) have been detected by in situ hybridization and immunohistochemistry in the macrophages infiltrating the media.25–27 In apoE0 mice, MMP-3, -9, -12, and -13 have been detected in cells at the base of the plaque, in infiltrating macrophages, and in the inflamed adventitia surrounding sites of medial destruction.23
Direct evidence for the role of MMPs in medial degradation associated with atherosclerosis was first given in a study by Carmeliet and colleagues23 with the use of apoE0 mice deficient in the urokinase-type plasminogen activator. These mice were found to be resistant to medial degeneration and aneurysm formation. Because plasmin cannot degrade fibrillar collagen or elastin, the main proteins of the media, it is very likely that resistance to medial degradation in urokinase-type plasminogen activator–deficient mice was due to a lack of plasmin-activated MMPs in the atherosclerotic lesions. Furthermore, apoE0 mice deficient in stromelysin-1 (MMP-3) have larger atherosclerotic lesions but reduced aneurysm formation, suggesting that MMP-3 is involved in the matrix degradation of the vessel wall.28
Our study provides further direct insights for the role of TIMP-1 and MMPs in medial degradation and pseudo-microaneurysm formation in atherosclerosis. Because TIMP-1 has been shown to be overexpressed in medial degradation during aortic aneurysm,25 in which it colocalizes to the vascular smooth muscle cells,25,26 it is likely that deficiency in TIMP-1 results in a decreased inhibition of active MMPs at site of disruption. We can thus hypothesize that the increased degradation of the media in our Timp-1–knockout mice is a consequence of augmented MMP activity in the atherosclerotic lesions. The lack of true aneurysm formation suggests that a concomitant elevation in blood pressure resulting in altered hemodynamic forces is necessary for the development of dilatation, as has been seen in other studies.29
Other animal models have provided insight into the role of MMPs in the pathological disruption of the media. Mice deficient in gelatinase B (MMP-9) are resistant to an elastase-induced model of aortic aneurysm.30 Experiments in rats demonstrated that the retroviral overexpression of TIMP-1 in smooth muscle cells prevented the degradation of the media, a process associated with decreased MMP activity.13
Because we did not detect differences in plaque size, macrophage content, and collagen deposition between controls and Timp-1-/0 animals after 10 weeks of high-fat diet, it appears that TIMP-1 deficiency alone does not significantly alter plaque evolution or progression. In a previous study, we have shown that increased expression of the human enzyme MMP-1 (interstitial collagenase) in plaques led to decreased lesion formation in apoE0 animals.19 However, mice do not normally express MMP-1 and, therefore, loss of TIMP-1 would not lead to increased MMP-1 activity within the plaque of apoE0 mice, although an increase in interstitial collagenase activity may occur because of MMP-13. From our present study, it appears that the increase in MMP activity because of the loss of TIMP-1 is insufficient to result in a significant difference in lesion size after 10 weeks of high-fat diet. At the level of detection for the in situ zymography, no differences in gelatinolytic activity were detected between apoE0 controls and Timp-1–knockout mice.
Our data may also indicate that other inhibitors of MMPs in the atherosclerotic lesion, such as TIMP-2, TIMP–3, and the tissue factor pathway inhibitor-2,31 have a more essential role than TIMP-1 in the regulation of MMPs during plaque evolution. In addition, because TIMP-1 does not affect MMP-14 activity, it is possible that this proteinase could be critical in lesion remodeling through its ability to activate proMMP-2 and digest fibrillar collagens.32 Finally, the absence of a difference in plaque size and quality may imply that other classes of proteinases, such as cathepsins S and K,33 which are unaffected by TIMP-1, have an important contribution to plaque progression.
A similar study to the one presently reported was recently published by Silence et al.34 These authors demonstrate that the apoE0 mice deficient in TIMP-1 have an increase in aneurysm formation and smaller atherosclerotic lesions after 30 weeks of a high-fat diet. Because we did not detect any difference in plaque size after 10 weeks of the diet, it is probable that the effect of TIMP-1 deficiency on plaque development becomes significant only in very advanced lesions. The medial disruptions they described were identical to the lesions we have observed, but we refer to them more representatively as pseudo-microaneurysms, as opposed to aneurysms, because of the lack of dilation of the aortic vessel wall.
In conclusion, our study demonstrates that the aortic atherosclerotic lesions of apoE0 mice deficient in TIMP-1 have an increase in medial degradation with pseudo-microaneurysm formation. This phenotype is likely attributed to a decreased inhibition of active MMPs at the sites of disruption. Our data thus strongly suggest that during atherosclerosis, TIMP-1 plays a key role in inhibiting and regulating the activity of MMPs that are involved in the degradation of the media underlying the atheroma.
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Acknowledgments |
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This work was supported by American Heart Association grant 9850025T and National Institutes of Health RO1 grant AG16994-0 (Dr D’Armiento) and American Heart Association Heritage Affiliate postdoctoral fellowship 0020232T (Dr Lemaître). The authors thank Tina Zelonina and Victor Nieves (Columbia University, NY) for their technical assistance, and Dr Alan R. Tall (Columbia University, NY) for his critical review of the manuscript.
Received April 17, 2002; revision received September 23, 2002; accepted September 23, 2002.
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 M.L. Eigenbrodt, Z. Bursac, E.P. Eigenbrodt, D.J. Couper, R.E. Tracy, and J.L. Mehta Mathematical estimation of the potential effect of vascular remodelling/dilatation on B-mode ultrasound intima-medial thickness QJM, November 1, 2004; 97(11): 729 - 737. [Abstract] [Full Text] [PDF]
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S. M. Lessner, D. E. Martinson, and Z. S. Galis Compensatory Vascular Remodeling During Atherosclerotic Lesion Growth Depends on Matrix Metalloproteinase-9 Activity Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2123 - 2129. [Abstract] [Full Text] [PDF]
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J. S. Ikonomidis, W. C. Gibson, J. E. Butler, D. M. McClister, S. E. Sweterlitsch, R. P. Thompson, R. Mukherjee, and F. G. Spinale Effects of Deletion of the Tissue Inhibitor of Matrix Metalloproteinases-1 Gene on the Progression of Murine Thoracic Aortic Aneurysms Circulation, September 14, 2004; 110(11_suppl_1): II-268 - II-273. [Abstract] [Full Text] [PDF]
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G. K. Owens, M. S. Kumar, and B. R. Wamhoff Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease Physiol Rev, July 1, 2004; 84(3): 767 - 801. [Abstract] [Full Text] [PDF]
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A. Luttun, E. Lutgens, A. Manderveld, K. Maris, D. Collen, P. Carmeliet, and L. Moons Loss of Matrix Metalloproteinase-9 or Matrix Metalloproteinase-12 Protects Apolipoprotein E-Deficient Mice Against Atherosclerotic Media Destruction but Differentially Affects Plaque Growth Circulation, March 23, 2004; 109(11): 1408 - 1414. [Abstract] [Full Text] [PDF]
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A. Daugherty and L. A. Cassis Mouse Models of Abdominal Aortic Aneurysms Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 429 - 434. [Abstract] [Full Text]
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E. Lutgens, R.-J. van Suylen, B. C. Faber, M. J. Gijbels, P. M. Eurlings, A.-P. Bijnens, K. B. Cleutjens, S. Heeneman, and M. J.A.P. Daemen Atherosclerotic Plaque Rupture: Local or Systemic Process? Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2123 - 2130. [Abstract] [Full Text] [PDF]
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