Active matrix metalloproteinases 3 and 9 are independently associated with coronary artery in-stent restenosis

doi:10.1016/j.atherosclerosis.2009.05.036

Atherosclerosis

Volume 207, Issue 2, December 2009, Pages 603-607

https://doi.org/10.1016/j.atherosclerosis.2009.05.036 Get rights and content

Abstract

Objective

This study aimed to determine whether plasma levels of active matrix metalloproteinases (MMP) are predictors of in-stent restenosis (ISR) in New Zealand patients treated with bare-metal coronary stents.

Methods

A group of 152 patients with a history of ISR were compared with 151 symptom free 1-year post-stenting patients (non-ISR). Demographic and angiographic characteristics were collected. Plasma samples were analyzed for the active forms of MMP-1, -2, -3 and -9 as well as tissue inhibitor of metalloproteinases (TIMP-1) using ELISA-based isoform sensitive assays.

Results

Both active MMP-9 and active MMP-3 were independently associated with history of ISR. Elevated levels of both active MMP-3 and -9 had an adjusted odds ratio of 11.8 (95% CI: 4–35, p < 0.0001) for association with ISR, with 37% of ISR patients having such levels versus 11% on non-ISR. The addition of both of the MMP biomarkers significantly increased the area under the curve (AUC) of a receiver operator characteristic (ROC) analysis incorporating the significant demographic and angiographic variables (AUC 0.85 versus 0.78, p < 0.005).

Conclusion

Measures of plasma active MMP isoforms appear to be independently associated with ISR, and assessment of multiple MMP markers yields cumulative utility.

Introduction

In-stent restenosis (ISR) is regarded to be a major limiting factor of bare-metal coronary stenting [1], and while drug-eluting stents have reduced the rates of ISR, they are still significant [2]. Concern over very late/late stent thrombosis and bleeding with prolonged dual antiplatelet therapy has led to proposals that patients be risk profiled for selective use of drug-eluting stents [3]. The ability to more reliably predict the risk of ISR would be an important part of the decision making process to optimise patient management.

Models of arterial injury have revealed that matrix metalloproteinase (MMP) genes [4] and plasma concentrations are up-regulated in a time and location specific manner [5], [6]. Over-expression of tissue inhibitors of metalloproteinases (TIMPs) reduced smooth muscle cell (SMC) migration [7], and MMP-9 in particular is critical for the proliferation and migration of SMC [8]. The levels of various MMPs appear to be raised after stent implantation in humans [9], [10], and there is some evidence that MMPs are linked to restenosis of carotid endarterectomy [11] and after coronary stenting [12]. The association of MMPs and vascular injury is consistent in both animal and human studies, and suggest that levels of MMPs may be increased with the development of restenosis after coronary stent implantation.

In this study, circulating plasma levels of four active isoforms (MMP-1, -2, -3 and -9) and TIMP-1 were assayed in patients who had previously undergone bare-metal stent placement to determine if individual or combined levels of these isoforms were predictors of ISR.

Section snippets

Subjects

Patients with coronary bare-metal stent placements were recruited retrospectively from the Dunedin Hospital Cardiology Clinical database as previously described [13]. A group of 152 patients with a history of symptomatic, angiographically proven, ISR were compared with 151 patients who were angina free for more than 1 year following their stent placement (non-ISR). At the time of study all subjects in the ISR group had undergone revascularisation with either repeat percutaneous intervention or

Demographic factors associated with ISR

Patients with ISR had significantly greater waist circumference, BMI and high-sensitivity CRP, significantly lower HDL-cholesterol and were more medicated compared with those with no history of ISR (online Table 1). Patients with ISR also had a higher rate of triple vessel disease and significantly more complex ACC/AHA lesion score and stent characteristics (online Table 2). There were no other significant differences between the two patient groups demographic variables.

Plasma MMP levels

Plasma active MMP-3 and

Discussion

This study evaluated circulating levels of multiple MMP related markers in patients who had undergone coronary bare-metal stent placement, with a specific emphasis on the active forms of MMP-1, -2, -3 and -9. Circulating levels of active forms of MMP-3 and -9 were significantly higher in patients with a history of ISR. In addition there appeared to be an additive association with regard to patients with multiple ISR lesions. Importantly, these associations remained significant despite

Acknowledgements

We gratefully acknowledge the funding support of the Heart Foundation of New Zealand. The assistance of Mr Andrew Gray with the statistical analysis in this study is greatly appreciated.

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The Profile of Circulating Matrix Metalloproteinases in Patients Undergoing Lower Limb Endovascular Interventions for Peripheral Arterial Disease
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Citation Excerpt :
Although there are some data investigating the temporal relationship between MMPs and angioplasty in the coronary16–20 and, less so, the carotid21–24 circulation, little is known with regard to the local or systemic release of MMPs before, during, and after peripheral interventional procedures in PAD patients. A positive correlation between MMP-2, MMP-3, and MMP-9 activity and restenosis has been shown in patients undergoing coronary angioplasty.16,18 Another study suggested that MMP-9 levels may be also used as an indicator for restenosis following cervical and intracranial angioplasty and stenting.22
Matrix metalloproteinases (MMPs) play a significant role in the development and progression of atherosclerotic vascular disease. We aimed to document the profile of circulating MMPs in peripheral arterial disease (PAD) patients undergoing lower limb endovascular revascularization.
A total of 46 patients (37 male; mean age 66 ± 11 years) undergoing elective lower limb percutaneous revascularization (angioplasty/stent) for symptomatic PAD were recruited from 2 vascular centers. Exclusion criteria were: acute limb ischemia, active infection and/or wet gangrene, liver disease, end-stage renal disease, and cancer. Patients having open revascularization or hybrid (open combined with endovascular) procedures were also excluded. Peripheral venous blood samples were taken on admission and 24 hrs after the procedure. Levels of MMP-2, MMP-3, MMP-7, and MMP-9 were measured along with tissue inhibitors of MMPs (TIMPs) 1 and 2.
Compared to baseline values, there was a significant elevation in serum MMP-3 (P = 0.014) and MMP-7 (P = 0.008) levels, whereas serum MMP-9 showed a nonsignificant trend to increase (P = 0.169). On the other hand, no significant alterations were found 24 hrs after angioplasty/stenting with regard to the MMP-2 level and TIMP-1 and 2 levels.
This study documented the periprocedural profile of circulating MMPs in patients undergoing angioplasty/stenting for PAD. The implications of increased MMP-3 and MMP-7 activity after peripheral endovascular interventions and their potential clinical relevance require further investigation.
Vascular smooth muscle cell phenotypic modulation and the extracellular matrix
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Blockade of MMPs with a general inhibitors or by specific MMP knockout have all been shown to reduce neointima formation in arterial injury models.36,37 Moreover, in patients, active MMP-3 and MMP-9 were associated with a history of in-stent restenosis38 while serum levels of MMP-2 and MMP-9 are associated with increased restenosis rates after implantation of drug-eluting stents.39 Restenosis after angioplasty is principally due to neointimal hyperplasia stemming from de-differentiation of vascular smooth muscle cells.
Intervascular stents provide clinical benefits in preventing occlusive coronary artery disease after angioplasty, but intimal hyperplasia and restenosis after stent implantation remains an unresolved problem. Vascular smooth muscle cells (VSMCs), the main component of medial layer of arteries, play an important role in neointimal hyperplasia. After arterial injury, quiescent, contractile VSMCs undergo a change in phenotype; they proliferate and migrate from the media to the intima. It has been shown that the extracellular matrix (ECM) plays a key role in tissue formation, homeostasis and repair. The adhesion, proliferation, and migration of VSMCs are strongly influenced by interaction with ECM components including proteoglycans, glycoproteins such as fibronectin, collagen, elastic fibers (laminae). This interaction is further diversified under the influence of multiple transmembrane receptors and matrix proteinases. Hence, the coordinated regulation of VSMC function by these matrix components is an essential process for controlling the development and remodeling of the vascular system. Here the role of ECM in VSMC phenotypic modulation and neointimal hyperplasia will be reviewed.
Matrix Metalloproteinases in Biologic Samples
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A possible explanation for this relates to the different capture antibodies used, with at least one commercial supplier stating that their selected capture antibody has a lower cross-reactivity with MMPs that are bound to a TIMP [59,60]. Regardless of the reasons, even though most of the various conventional ELISA and ELISA-based activity assays are intrinsically reliable [58], with coefficients of variance generally well below 10% [61], their respective measures of MMP levels are unlikely to be directly comparable. It stands to reason that the most biologically important isoform is that which is endogenously active.
Matrix metalloproteinases (MMPs) are an important class of endopeptidases, having a role in a diverse range of physiological and pathological processes. This chapter provides an overview of the key regulatory processes in MMP production and activation. The common techniques used to assess MMP activity are discussed and their various strengths and weaknesses presented. This comparison of methodologies is specifically intended to aid any investigator who wishes to determine the most appropriate analytical method for their future studies because any investigation of MMPs in biological samples should be cognizant of the key mechanisms influencing the expression and activity of these proteinases. The endogenous, preanalytic and analytic chemistry of MMP activation influences the interpretation of the various techniques widely employed throughout the literature. Therefore, the ability to accurately evaluate the true endogenous activity of MMPs is heavily dependent on a clear understanding of these processes.
MMP-3 (5A/6A) polymorphism does not influence human smooth muscle cell invasion
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It is regarded as an important regulator not only due to its broad substrate specificity but also due to its ability to activate other MMPs [3]. High levels of MMP-3 have been detected in atherosclerotic plaques and in SMC of atherosclerotic coronary arteries [4, 5], and are associated with an increased risk of in-stent restenosis [6]. The expression of the MMP-3 gene is tightly regulated at the transcriptional level where the promoter of the gene responds to a number of growth factors and cytokines.
Stromelysin (MMP-3) is an important regulator of vascular smooth muscle cell (SMC) invasion, a key contributor to saphenous vein (SV) bypass graft failure. The 5A allele of the common -1612 MMP-3 5A/6A promoter polymorphism reportedly confers increased promoter activity, MMP-3 tissue expression, and susceptibility to a number of vascular pathologies. The aim of this study was to determine whether the MMP-3 5A/6A polymorphism directly influences endogenous MMP-3 expression levels and, consequently, cell invasion, in SV-derived SMC cultured from patients with different genotypes.
Genotyping of 226 patients revealed -1612 MMP-3 5A/6A genotype frequencies of 20.8% 5A/5A, 52.7% 5A/6A, and 26.5% 6A/6A. Using a standardized, controlled protocol, we investigated cytokine- and growth factor-induced MMP-3 expression (real-time polymerase chain reaction [RT-PCR], ELISA) and SV-SMC invasion (Boyden chamber with Matrigel barrier) using cultured SV-SMC from patients with different MMP-3 genotypes.
Despite observing a strong correlation between MMP-3 mRNA levels and MMP-3 protein secretion, no significant differences were apparent in MMP-3 expression levels or cell invasion between cells with different MMP-3 5A/6A genotypes.
Our data suggest that the MMP-3 5A/6A promoter polymorphism in isolation does not influence levels of MMP-3 secretion or cellular invasion in human SV-SMC.
Seasonal variation and stability of matrix metalloproteinase-9 activity and tissue inhibitor of matrix metalloproteinase-1 with storage at -80°C
2011, Clinical Biochemistry
Citation Excerpt :
A number of long-term studies have examined the role of MMPs in the prediction of cardiovascular events. A number of reports in which samples had been stored for around two years found that pro-MMP-9 in EDTA plasma read between 20 ng/mL and 70 ng/mL [7,8]. One group has reported high pro-MMP-9 (> 500 ng/mL) levels in serum for up to 16 years [9].
To determine whether active matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 displayed seasonal variation and were stable in storage.
Plasma active MMP-9 and TIMP-1 were measured at three time-points in 163 individuals.
There was no evidence for seasonal variation or declining levels for up to three years of storage at − 80 °C.
Active MMP-9 and TIMP-1 appear to be stable seasonally, and in storage for at least three years.
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View all citing articles on Scopus

View full text

Active matrix metalloproteinases 3 and 9 are independently associated with coronary artery in-stent restenosis

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Subjects

Demographic factors associated with ISR

Plasma MMP levels

Discussion

Acknowledgements

Int J Cardiol

Atherosclerosis

Int J Cardiol

J Am Coll Cardiol

Atherosclerosis

Thromb Res

Lancet

Am Heart J

Lancet

Coronary artery stents

JAMA

Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis

Circulation

Risk profiling patients for selective use of drug-eluting stents is warranted

Nat Clin Pract Cardiovasc Med

Induction of collagenase and stromelysin gene expression by mechanical injury in a vascular smooth muscle-derived cell line

J Cell Physiol

Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat

Circ Res

Temporal and topographic matrix metalloproteinase expression after vascular injury in mice

Thromb Haemost

Overexpression of tissue inhibitor of matrix metalloproteinase-1 inhibits vascular smooth muscle cell functions in vitro and in vivo

Circ Res