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(Stroke. 2004;35:1310.)
© 2004 American Heart Association, Inc.

Original Contributions

Differences in Matrix Metalloproteinase-1 and Matrix Metalloproteinase-12 Transcript Levels Among Carotid Atherosclerotic Plaques With Different Histopathological Characteristics

Angharad R. Morgan, BSc; Kittipan Rerkasem, MD; Patrick J. Gallagher, MD, PhD, FRCP; Baiping Zhang, DPhil; Gareth E. Morris, DM, FRCS; Philip C. Calder, PhD; Robert F. Grimble, PhD; Per Eriksson, PhD; William L. McPheat, PhD; Clifford P. Shearman, MS, FRCS Shu Ye, MD, PhD

From Human Genetics Division (A.R.M., B.Z., S.Y.), Department of Pathology (P.J.G.), Institute of Human Nutrition (P.C.C., R.F.G.), School of Medicine, University of Southampton, UK; Department of Vascular Surgery (K.R., G.E.M., C.P.S.), Southampton General Hospital, UK; Atherosclerosis Research Unit (P.E.), Karolinska Hospital, Sweden; Molecular Pharmacology (W.L.M.), AstraZeneca, Mölndal, Sweden; Department of Surgery (K.R.), Faculty of Medicine, Chiang Mai University, Thailand.

Correspondence to Shu Ye, Human Genetics Division, School of Medicine, University of Southampton, Duthie Building (808), Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. E-mail Shu.Ye{at}soton.ac.uk

	Abstract

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Background and Purpose— Previous studies have shown that atherosclerotic lesions express a number of matrix metalloproteinases (MMPs). Here we investigated whether transcript levels of MMP-1, -3, -7, -9, and -12 in carotid atherosclerotic plaques were correlated with histological features and clinical manifestations.

Methods— Atherosclerotic plaques (n=50) removed from patients undergoing carotid endarterectomy were classified histologically using a system proposed by Virmani et al, and MMP-1, -3, -7, -9, and -12 transcript levels in these tissues were quantified by real-time reverse-transcriptase polymerase chain reaction.

Results— Compared to plaques with a thick fibrous cap, those with a thin cap had a 7.8-fold higher MMP-1 transcript level (P=0.006). MMP-3, -7, and -12 were 1.5-fold, 1.8-fold, and 2.1-fold, respectively, higher in thin cap plaques, but the differences did not reach statistical significance. MMP-12 transcript levels were significantly increased in ruptured plaques compared with lesions without cap disruption (P=0.001). MMP-9 transcript levels were similar among the different types of lesion. MMP-1 and -12 transcript levels were significantly higher in plaques from patients with amaurosis fugax, than in those from asymptomatic patients (P=0.029 and P=0.008 for MMP-1 and MMP-12, respectively), than in those from patients with stroke (P=0.027 and P=0.001, respectively), and than in those from patients with transient ischemic attack (P=0.046 and P=0.008, respectively).

Conclusions— These data support a role of MMP-1 and -12 in determining atherosclerotic plaque stability.

Key Words: carotid arteries • atherosclerosis • metalloproteinases • gene expression

	Introduction

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Atherogenesis is a chronic, progressive process that may span several decades.¹ In a histological classification system proposed by the American Heart Association (AHA), atherosclerotic lesions are divided into 6 types representing different stages of the disease.² A modification of this system has been proposed by Virmani et al³ and endorsed by Stary,⁴ differentiating advanced lesions into those with a thick fibrous cap and those with a thin one. Atherosclerotic plaques with a thin fibrous cap are considered to be prone to rupture, which can result in an acute ischemic event, whereas plaques with a thick cap are more stable and have a lower complication rate.⁵

The formation and progression of atherosclerotic lesions involves degradation of vascular matrix proteins and remodeling of the vascular wall.⁵ Macrophages in atherosclerotic lesions produce a number of matrix metalloproteinases (MMPs).^6–10 These enzymes are capable of degrading various matrix proteins¹¹ and may play an important role in atherosclerotic lesion development and progression. Overexpression of these enzymes in advanced lesions may contribute to thinning of the plaque cap and the development of ischemic events resulting from plaque rupture.¹²

In this study, we measured the transcript levels of MMP-1, -3, -7, -9, and -12 in carotid atherosclerotic plaques to investigate whether they were expressed at different levels in different lesion types and whether their expression levels correlated with clinical manifestations.

	Materials and Methods

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Carotid Atherosclerotic Specimens
Atherosclerotic plaques (n=50) removed from patients undergoing carotid endarterectomy at Southampton General Hospital were subjected to histopathological examinations and quantifications for MMP-1, -3, -7, -9, and -12 transcripts were performed as described. Immediately after a plaque was removed from the patient, it was divided into multiple transverse sections. The plaque section in the internal carotid artery closest to the bifurcation was immediately snap-frozen in liquid nitrogen and then stored at –80°C before extraction of RNA for MMP transcript measurement. The plaque section in the common carotid artery closest to the bifurcation was fixed in formaldehyde and then embedded in paraffin wax for subsequent histological examination. The study was approved by the local research ethics committee and all subjects gave written consent.

Histopathological Examinations
The atherosclerotic plaques were classified histologically using a system proposed by Virmani et al³ and endorsed by Stary.⁴ In brief, pathological intimal thickening was defined as a lesion containing smooth muscle cells and extracellular lipids without necrotic core. Fibrous cap atheromas were lesions with a well-formed necrotic core and an overlying fibrous cap thicker than 200 µm. Thin fibrous cap atheromas were lesions with a thin (<200 µm) fibrous cap and an underlying necrotic core. Ruptured plaques were fibroatheromas with cap disruption with an underlying necrotic core.³

Quantification of MMP-1, -3, -7, -9, and -12 Transcripts
Total cellular RNA was extracted using an RNAgents total RNA isolation system (Promega). The mRNA fraction of the total cellular RNA was converted to cDNA by reverse transcription with an oligo-dT₁₅ primer, moloney murine leukemia virus reverse-transcriptase (Promega) and RNasin ribonuclease inhibitor (Promega). Real-time polymerase chain reaction (PCR) was performed using an ABI Prism 7700 Sequence Detection System (Applied Biosystems). PCR primers and probes (Table 1) were designed using the Primer Express program (Applied Biosystems), with the forward and reserve primers located in different exons and the probe spanning an intron-exon boundary. PCR products for MMP-1 and -3 were detected using the SYBR Green method and those for MMP-7, -9, and -12 were detected using probes labeled with reporter day FAM (6-carboxy-fluorescein) at the 5' end and quencher dye TAMRA (6-carboxy-tetramethyl-rhodamine) at the 3' end. Specificity of the PCR products was verified by agarose gel electrophoresis. The 2^–Ct method described by Livak and Schmittgen¹³ was used to analyze the results. In brief, the Ct (threshold cycle) value of an MMP gene was subtracted from the Ct value of a reference housekeeping gene (36B4, acidic ribosomal phosphoprotein P0)^14,15 to standardize for the amounts of RNA template and efficiencies of reverse transcription. The resulting change in Ct values was then converted to a linear form using 2^–Ct and used in subsequent statistical analysis.

View this table: [in this window] [in a new window]   TABLE 1. PCR Primers and Probes

Statistical Analyses
Correlation analysis was performed to calculate Pearson correlation coefficients between the MMP transcript levels. One-way ANOVA analyses were performed to examine differences in MMP transcript levels among different types of atherosclerotic lesion and among patient groups with different manifestations. If a 1-way ANOVA analysis showed that there was a difference among the group means, post hoc pair-wise multiple comparisons (least significant difference) were performed to determine which means differ. The statistical analyses were performed using the SPSS software (version 11.5, SPSS Inc), with the exception of the linear trend test presented in Table 3, which was performed using the StatsDirect program (StatsDirect Ltd). P<0.05 was considered significant.

View this table: [in this window] [in a new window]   TABLE 3. Clinical Manifestations Versus Types of Atherosclerotic Plaque

	Results

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Demographic and clinical features of the subjects are summarized in Table 2. Of the 50 atherosclerotic plaques studied, there were 5 early lesions (pathological intimal thickening), 33 fibrous cap atheromas, 9 thin fibrous cap atheromas, and 3 ruptured plaques.³

View this table: [in this window] [in a new window]   TABLE 2. Characteristics of Subjects and Atherosclerotic Plaques

MMP Transcript Levels in Different Types of Atherosclerotic Lesions
MMP-1, -3, -7, -9, and -12 transcript levels in the atherosclerotic plaques were measured by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) using an ABI Prism 7700 Sequence Detection System. A representative output from the system is shown in Figure 1. The mean MMP-1, -3, -7, -9, and -12 transcript levels in pathological intimal thickening lesions, plaques with a thick fibrous cap, plaques with a thin fibrous cap, and ruptured plaques, classified according to the Virmani system^3,4 are shown in Figure 2. MMP-1 was 7.8-fold higher in those with a thin fibrous cap than in those with a thick fibrous cap (P=0.006). MMP-3, -7, and -12 were 1.5-fold, 1.8-fold, and 2.1-fold, higher in thin cap plaques, respectively, but the differences did not reach statistical significance. MMP-12 was significantly higher in ruptured plaques than in pathological thickening lesions (P=0.001), thick cap plaques (P<0.001), and thin cap plaques (P=0.007). MMP-9 transcript levels were similar in all 4 types of lesion.

View larger version (101K): [in this window] [in a new window]   Figure 1. Representative real-time RT-PCR results. The graph shows fluorescence signals accumulated at different PCR cycles. Each curve represents 1 PCR.

View larger version (20K): [in this window] [in a new window]   Figure 2. MMP transcript levels in different types of atherosclerotic lesion. *Significantly higher in thin cap plaques than in thick cap plaques (P=0.006) and pathological intimal thickening (P=0.038). **Significantly higher in ruptured plaques compared with thick cap plaques (P<0.001), thin cap plaques (P=0.007), and pathological intimal thickening (P=0.001).

There were positive correlations between the levels of MMP-1, -7, and -12 transcripts, with a correlation coefficient (r) of 0.650 (P=0.001) between MMP-1 and -7, 0.653 (P<0.001) between MMP-1 and -12, and 0.785 (P<0.001) between MMP-7 and -12. There was also a nominal correlation between MMP-7 and -9 (r=0.419, P=0.046). In contrast, MMP-3 levels were not correlated with the levels of other MMPs.

MMP Transcript Levels in Atherosclerotic Plaques and Clinical Manifestations
Forty percent of early lesions (pathological intimal thickening) and 15.2% of plaques with a thick fibrous cap were asymptomatic, whereas all plaques with a thin fibrous cap and all ruptured plaques were symptomatic (Table 3). Amaurosis fugax was seen in 9.1% of patients with thick cap plaque, 22.2% of patients with thin cap plaque, 33.3% of patients with ruptured plaque, but in none of the patients with only pathological thickening (Table 3).

MMP-1 and -12 transcript levels were significantly higher in the plaques from patients with amaurosis fugax than in those from asymptomatic patients (P=0.029 and P=0.008 for MMP-1 and MMP-12, respectively; Figure 3), those from patients with stroke (P=0.027 and P=0.001, respectively; Figure 3), and those from patients with transient ischemic attack (P=0.046 and P=0.008, respectively; Figure 3). MMP-1 transcript levels were higher also in plaques from patients with stroke and plaques from patients with transient ischemic attack than in plaques from asymptomatic patients (Figure 3), but the differences did not reach statistical significance. There was no significant association between clinical manifestations and MMP-3, -7, and -9 transcript levels (Figure 3).

View larger version (20K): [in this window] [in a new window]   Figure 3. MMP transcript levels in atherosclerotic plaques from patients with different symptoms. *Significantly higher in the plaques from patients with amaurosis fugax than in those from asymptomatic patients (P=0.029), those from patients with stroke (P=0.027), and those from patients with transient ischemic attack (P=0.046). **Significantly higher in the plaques from patients with amaurosis fugax compared with those from asymptomatic patients (P=0.008), those from patients with stroke (P=0.001), and those from patients with transient ischemic attack (P=0.008).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The aims of this study were to compare the levels of gene expression of a number of key MMPs between different types of atherosclerotic lesion and to relate these to clinical manifestations. Using the quantitative real-time RT-PCR method, we found that MMP-1 transcript levels were nearly 8-fold higher in thin cap plaques than in thick cap plaques, which supports the finding of Sukhova et al¹² who showed that thin cap plaques had higher MMP-1 and -13 protein levels than thick cap plaques. We also observed 1.5- to 2-fold higher MMP-3, -7, and -12 transcript levels in thin cap plaques compared with thick cap plaques, although these differences did not reach statistical significance. In addition, the expression of MMP-12 was found to be significantly higher in ruptured atherosclerotic plaques than in lesions without cap disruption. In contrast, the expression levels of MMP-9, which have been suggested to be related to plaque instability, were found to be similar among the different types of lesion. Taken together, these observations indicate a link of MMP-1 and possibly MMP-12, but not MMP-9, with plaque instability. These observations are in agreement with results from a recent study using the gene knockout technique, which showed that the frequency of plaque rupture is reduced in MMP-12 knockout mice but surprisingly is increased in MMP-9 knockout mice, suggesting that members of the MMP family have diverse effects on plaque stability.¹⁶

Among the MMPs examined in this study, only MMP-9 was found to be expressed at considerable levels in early lesions, ie, pathological intimal thickening lesions. It has been shown that smooth muscle cells in atherosclerotic lesions express MMP-9.⁹ Because the main constituent of pathological intimal thickening lesions is smooth muscle cells, the observation that MMP-9 but not the other MMPs studied is expressed at significant levels in these early lesions is consistent with findings from other studies that MMP-9 plays a major role in vascular smooth muscle cell migration and proliferation in atherogenesis.^17,18 Each vascular smooth muscle cell is surrounded by a basement membrane. Migration of smooth muscle cells entails breakdown of this extracellular barrier, and this is dependent on the secretion of MMP-9, which can degrade the major constituent protein, ie, type IV collagen, in the basement membrane.¹⁷

The results of this study also suggest an association between increased MMP-1 and -12 expression and the development of amaurosis fugax in patients with carotid atherosclerosis. Although MMP-1 transcript levels were also higher in plaques from patients with stroke and in those from patients with transient ischemic attack than they were in plaques from asymptomatic patients, the differences did not reach statistical significance. The finding that there is an association of increased MMP-1 and -12 expression with the development of amaurosis fugax but that there is no significant association between the expression of these MMPs and the development of stroke and transient ischemic attack suggest that these different complications of carotid atherosclerosis might result from different mechanisms. Previous studies have suggested that the development of amaurosis fugax is a result of embolism caused by small emboli from ruptured carotid plaques, whereas the development of transient ischemic attack and stroke has more complicated mechanisms, relating not only to carotid plaque rupture but also to the degrees of intracranial stenosis and impaired collateral cerebral circulation.^19,20 This could explain the observation of this study that amaurosis fugax, but not stroke or transient ischemic attack, was significantly associated with increased MMP-1 and MMP-12 expression and unstable carotid atherosclerotic plaques.

The focus of this study was on gene expression levels of a number of key MMPs in different types of atherosclerotic lesion and their relationships with clinical manifestations. A relevant question as to what types of cell in the atherosclerotic lesion express these MMPs has been addressed by other studies. It has been shown that MMP-1, -3, -7, -9, and -12 are expressed primarily by macrophages in the shoulder region of the atherosclerotic plaque and the border between the lipid core and overlying fibrous areas.^6,7,10 In addition, previous studies have also shown that MMP mRNA levels correspond to the levels of MMP proteins and proteolytic activities in atherosclerotic lesions.^7,12

It is likely that plaque rupture involves a battery of different proteases, and therefore further studies are required to examine a larger set of candidate genes for plaque instability. Strong candidates would include the other 2 collagenases, ie, MMP-8 and MMP-13, both of which have been shown to be expressed in atherosclerotic lesions, and the latter has been found to be expressed at higher levels in lipid-rich plaques.^12,21 In addition to MMPs, serine and cysteine proteases might also have an impact on atherosclerotic plaque stability. Recent studies have revealed that members of the serine proteinase family, such as neutrophil elastase²¹ and plasminogen activators,²² and members of the cysteine proteinase family, such as cathepsins B, K, L, and S,^23,24 are expressed in atherosclerotic plaques and might also have an impact on plaque stability.^23–26

Atherosclerosis is a systemic disease and patients often have multiple lesions in different arteries. In the present study, only 1 carotid plaque per patient was available for examination. It is possible that additional atherosclerotic plaques were present in the vasculature in some of these patients, and they might have different MMP expression profiles and histopathological features from the plaques examined in this study. However, the carotid plaques examined in this study were the plaques that prompted the carotid endarterectomy operations and seemed likely responsible for the clinical symptoms in these patients.

In summary, the results of this study support a role of MMP-1, and possibly also MMP-12, in determining atherosclerotic plaque stability and the development of amaurosis fugax. It is conceivable that inhibiting these MMPs could stabilize atherosclerotic plaques and improve the clinical outcome, and it is encouraging that a prospective, randomized, double-blind trial has shown that doxycycline can reduce MMP-1 expression in carotid atherosclerotic plaques.²⁷

	Acknowledgments

 
This work was supported by the British Heart Foundation (PG98/183, PG98/192, PG/2001105), the UK Medical Research Council (G78/7025), the Food Standards Agency (ANO238), AstraZeneca, the Swedish Research Council (12660), AFA Insurance, and the King Gustaf V and Queen Victoria Foundation. Kittipan Rerkasem was supported by the Faculty of Medicine, Chiang Mai University, and the Royal Thai Government. We thank Tina Nilsson and Charlotte Wenberg for their advice on and assistance with the MMP quantification assays.

Received October 23, 2003; revision received January 20, 2004; accepted February 13, 2004.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993; 362: 801–809.[CrossRef][Medline] [Order article via Infotrieve]
2. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the committee on vascular lesions of the council on arteriosclerosis, American Heart Association. Circulation. 1995; 92: 1355–1374.[Abstract/Free Full Text]
3. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000; 20: 1262–1275.[Free Full Text]
4. Stary HC. Natural history and histological classification of atherosclerotic lesions: an update. Arterioscler Thromb Vasc Biol. 2000; 20: 1177–1178.[Free Full Text]
5. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995; 91: 2844–2850.[Free Full Text]
6. Henney AM, Wakeley PR, Davies MJ, Foster K, Hembry R, Murphy G, Humphries S. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci U S A. 1991; 88: 8154–8158.[Abstract/Free Full Text]
7. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994; 94: 2493–2503.[Medline] [Order article via Infotrieve]
8. Nikkari ST, O’Brien KD, Ferguson M, Hatsukami T, Welgus HG, Alpers CE, Clowes AW. Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis. Circulation. 1995; 92: 1393–1398.[Abstract/Free Full Text]
9. Brown DL, Hibbs MS, Kearney M, Loushin C, Isner JM. Identification of 92-kD gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis withunstable angina. Circulation. 1995; 91: 2125–2131.[Abstract/Free Full Text]
10. Halpert I, Sires UI, Roby JD, Potter-Perigo S, Wight TN, Shapiro SD, Welgus HG, Wickline SA, Parks WC. Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc Natl Acad Sci U S A. 1996; 93: 9748–9753.[Abstract/Free Full Text]
11. Brinckerhoff CE, Matrisian LM. Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol. 2002; 3: 207–214.[CrossRef][Medline] [Order article via Infotrieve]
12. Sukhova GK, Schonbeck U, Rabkin E, Schoen FJ, Poole AR, Billinghurst RC, Libby P. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation. 1999; 99: 2503–2509.[Abstract/Free Full Text]
13. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(–C(T)) method. Methods. 2001; 25: 402–408.[CrossRef][Medline] [Order article via Infotrieve]
14. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003; 9: 213–219.[CrossRef][Medline] [Order article via Infotrieve]
15. Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, Tontonoz P. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem. 2002; 277: 11019–11025.[Abstract/Free Full Text]
16. Johnson J, George S, Newby A, Jackson CP. Matrix metalloproteinases-9 and -12 have opposite effects on atherosclerotic plaque stability. Atherosclerosis. 2003; 169: 199.[CrossRef]
17. Newby AC, Zaltsman AB. Molecular mechanisms in intimal hyperplasia. J Pathol. 2000; 190: 300–309.[CrossRef][Medline] [Order article via Infotrieve]
18. Galis ZS, Johnson C, Godin D, Magid R, Shipley JM, Senior RM, Ivan E. Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration arterial remodeling and geometrical. Circ Res. 2002; 91: 852–859.[Abstract/Free Full Text]
19. Dennis MS, Bamford JM, Sandercock PA, Warlow CP. A comparison of risk factors and prognosis for transient ischemic attacks and minor ischemic strokes. The Oxfordshire Community Stroke Project. Stroke. 1989; 20: 1494–1499.[Abstract/Free Full Text]
20. Tegos TJ, Sabetai MM, Nicolaides AN, Elatrozy TS, Dhanjil S, Thomas DJ. Patterns of cerebrovascular symptomatology associated with carotid atheroma. Eur J Neurol. 2000; 7: 499–508.[CrossRef][Medline] [Order article via Infotrieve]
21. Dollery CM, Owen CA, Sukhova GK, Krettek A, Shapiro SD, Libby P. Neutrophil elastase in human atherosclerotic plaques: production by macrophages. Circulation. 2003; 107: 2829–2836.[Abstract/Free Full Text]
22. Salame MY, Samani NJ, Masood I, deBono DP. Expression of the plasminogen activator system in the human vascular wall. Atherosclerosis. 2000; 152: 19–28.[CrossRef][Medline] [Order article via Infotrieve]
23. Sukhova GK, Shi GP, Simon DI, Chapman HA, Libby P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest. 1998; 102: 576–583.[Medline] [Order article via Infotrieve]
24. Jormsjo S, Wuttge DM, Sirsjo A, Whatling C, Hamsten A, Stemme S, Eriksson P. Differential expression of cysteine and aspartic proteases during progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol. 2002; 161: 939–945.[Abstract/Free Full Text]
25. Chen J, Tung CH, Mahmood U, Ntziachristos V, Gyurko R, Fishman, MC, Huang PL, Weissleder R. In vivo imaging of proteolytic activity in atherosclerosis. Circulation. 2002; 105: 2766–2771.[Abstract/Free Full Text]
26. Sukhova GK, Zhang Y, Pan JH, Wada Y, Yamamoto T, Naito M, Kodama T, Tsimikas S, Witztum JL, Lu ML, Sakara Y, Chin MT, Libby P, Shi, GP. Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003; 111: 897–906.[CrossRef][Medline] [Order article via Infotrieve]
27. Axisa B, Loftus IM, Naylor AR, Goodall S, Jones L, Bell PR, Thompson MM. Prospective, randomized, double-blind trial investigating the effect of doxycycline on matrix metalloproteinase expression within atherosclerotic carotid plaques. Stroke. 2002; 33: 2858–2864.[Abstract/Free Full Text]

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