Cardiovascular Research

Cardiovascular Research 2002 54(3):495-498; doi:10.1016/S0008-6363(02)00397-8
© 2002 by European Society of Cardiology

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Copyright © 2002, European Society of Cardiology

Matrix metalloproteinase-9 expression after myocardial infarction: physiological or pathological?

Matt M. Thompson^a,* and Iain B. Squire^b

^aDepartment of Surgery, University of Leicester, Leicester, UK
^bDepartment of Medicine and Therapeutics, University of Leicester, Leicester, UK

mattt11{at}aol.com

^* Corresponding author. Department of Surgery, RKCSB, Leicester Royal Infirmary, Leicester, LE2 7LX UK. Tel.: +44-11-6252-3252; fax: +44-11-6252-3179

Received 18 March 2002; accepted 18 March 2002

See article by Romanic et al. [24] (pages 549–558) in this issue.

Remodelling of the extracellular matrix is acknowledged to play a significant role in a number of vascular disorders including aneurysm formation, rupture of atherosclerotic plaques, and development of intimal hyperplasia [1,2]. In recent years, investigations of matrix biology have been applied to cardiac remodelling following acute myocardial infarction (MI). Left ventricular dilatation following MI is related to the extent of the ischaemic insult and subsequent healing of the infarct and surrounding tissue [3]. Whilst the process of postinfarct remodelling is incompletely understood, excessive degradation of extracellular matrix components appears to result in pathological cardiac remodelling, left ventricular dilatation and cardiac failure.

The major physiological regulators of the extracellular matrix are the matrix metalloproteinases (MMP), which have been implicated in the genesis of postinfarct ventricular failure [6]. The MMPs are a family of structurally related endopeptidases that have the ability to degrade all components of the extracellular matrix. The MMPs are classified according to their substrate specificity and presence of a transmembrane domain (collagenases, gelatinases, stromelysins and membrane type). The enzymes all share a degree of structural homology, contain a zinc atom at the catalytic site, and are inhibited by specific inhibitors (tissue inhibitors of matrix metalloproteinases—TIMP). Most MMPs require activation by proteolytic cleavage, and several serine proteases, particularly plasmin, play an important role in this process.

The most important MMPs with respect to the matrix composition of the vasculature are the collagenases and gelatinases. The collagenases (MMP-1, -8 and -13) have the ability to cleave collagen types I–III. The gelatinases (MMP-2, -9, -12) have broader substrate specificity for type IV collagen, elastin, aggrecan and vitronectin, but may degrade other elements of the extracellular matrix, including interstitial collagen [7], to varying degrees. (reviews of MMPs [4,5]).

	1 Expression of MMPs following MI

Top 1 Expression of MMPs... 2 Ventricular remodelling and... 3 Myocardial infarction and... 4 Clinical observations References

 
The effect of myocardial ischaemia and reperfusion on MMP expression has been studied experimentally. Utilising a rodent model, Peterson et al. [8] reported a differential time course of MMP expression following experimental infarction. In this study, the major rodent collagenases and gelatinases (MMP-2, -9, -13) increased in the first week following coronary occlusion, whilst MMP-8 and -14 (membrane type MMP-1) only became elevated when heart failure occurred. The time course of MMP-9 induction was further investigated by Romanic et al. [9], who demonstrated that MMP-9 was upregulated within 24 h of MI and that this rise was accompanied by a reduction in the physiological inhibitor of MMP-9, TIMP-1. Several other investigators have since revealed that MMP-9 is expressed within minutes of myocardial ischaemia [10,11], and that the increased MMP-9 appears to be neutrophil derived and in the active form [12].

Compelling experimental data have suggested that a spectrum of MMPs are overexpressed at different time periods following MI. The apparent implication of these observations was that MMP driven proteolysis might affect myocardial function following ischaemia, with respect to infarct development and tissue remodelling. However, the presence of increased MMP levels did not necessarily indicate a definitive role in these processes, as descriptive studies were not able to separate cause from effect. The recent availability of MMP inhibitors and genetically modified experimental models has allowed these pathological processes to be further detailed.

	2 Ventricular remodelling and MMP expression

Top 1 Expression of MMPs... 2 Ventricular remodelling and... 3 Myocardial infarction and... 4 Clinical observations References

 
Extrapolation from other studies would suggest that MMP induction following MI would play a significant role in infarct healing, matrix degradation, cell migration and ventricular remodelling. Rohde et al. [13] utilised a nonspecific MMP inhibitor to investigate the role of MI induced MMP expression in a murine model. Animals treated with broad spectrum MMP inhibition demonstrated reduced end diastolic and end systolic dimensions compared to controls. Interestingly, there was no difference in myocardial collagen content between the two groups.

Further support for a pathological role of MMP expression after MI was reported by Spinale et al. [14]. This group used a porcine model of congestive heart failure to demonstrate that MMP inhibition limited ventricular dilation and reduced wall stress. These findings suggested that MMP expression played a significant role in postinfarct remodelling, but did not determine which MMP subtype played the dominant role.

Evidence is now accumulating that MMP-9 may be crucial in the process of ventricular remodelling. Heymans et al. [15] observed that MMP-9 deficient mice had a reduced ventricular rupture rate following MI compared to wild type. In a similar series of experiments Ducharme et al. [16] demonstrated that MMP-9 deficient mice had attenuated ventricular dilatation and reduced collagen accumulation in response to left coronary occlusion. These changes were associated with reduced macrophage infiltration in the knockout animals. The findings that left ventricular dilation was reduced in the presence of lowered collagen concentrations suggested that a noncollagenolytic mechanism was responsible for regulation of postinfarct remodelling.

The therapeutic potential of this observation has been tested using selective MMP inhibition. Lindsey et al. [17] utilised MMP inhibition that spared major collagenase activity to investigate ventricular dilatation and infarct thickness following experimental infarction. Selective MMP inhibition reduced ventricular dilatation and infarct wall thinning, which confirmed that collagenase activity was not a major determinant of the remodelling process, and that by extension MMP-9 may be the dominant protease responsible for experimental ventricular failure.

	3 Myocardial infarction and MMP-9

Top 1 Expression of MMPs... 2 Ventricular remodelling and... 3 Myocardial infarction and... 4 Clinical observations References

 
Despite increasing interest in the significance of MMPs in postinfarct remodelling, relatively little attention has been given to their role in myocardial injury following an ischaemic insult. Previous investigations have demonstrated a relationship between MMP expression and ischaemia–reperfusion injury in the brain [18–20], liver [21], lung [22] and kidney [23].

In this issue of Cardiovascular Research, Romanic et al. [24] postulate a pivotal role for MMP-9 in MI. This important investigation revealed that targeted deletion of MMP-9 in a murine model of MI reduced infarct size by 35% in comparison to wild type mice with a similar ischaemic area. An attenuated activated neutrophil infiltrate and a rise in TIMP-1 accompanied this reduction in infarct size.

In this acute model, MMP-9 within the infarcted tissue was derived from neutrophils, which confirms previous observations [12]. The finding of a reduced neutrophil infiltrate within the ischaemic myocardium is potentially important, as it suggests that MMP-9 may be acting through at least two mechanisms. MMP-9 may act directly on ventricular tissue as a protease, but it may also facilitate neutrophil infiltration and degranulation, and exacerbate the ischaemic insult [25]. Previous studies in different pathological conditions have suggested that MMP-9 is an important determinant of neutrophil migration [26], as well as mediating direct tissue injury.

Cheung et al. [27] have suggested that MMP-2 expression may contribute to cardiac dysfunction following in vitro ischaemia, but there is little evidence at present to implicate other MMPs in the cardiac response to ischaemia.

	4 Clinical observations

Top 1 Expression of MMPs... 2 Ventricular remodelling and... 3 Myocardial infarction and... 4 Clinical observations References

 
Experimental data have suggested that MMPs, and in particular MMP-9, play a crucial role in both acute and chronic phases of the myocardial response to ischaemia. Differing cell types appear to predominate in the two phases, with neutrophil derived MMP-9 being elevated in acute infarction, and macrophage secretion more important in subsequent remodelling. Clearly, these data are of great significance as they suggest potential therapeutic strategies to improve outcome following myocardial ischaemia–reperfusion injury.

Familiarly, the problem will be translating novel experimental data into robust clinical findings. The main limitation in this setting is likely to be scant access to human tissue following MI, with which to document changes in proteolytic activity and the cardiac extracellular matrix. It is possible that these difficulties may be partially overcome by quantifying plasma levels of MMPs following cardiac events. In 1988, Kai et al. [28] observed an immediate threefold elevation in systemic plasma levels of MMP-9 in patients with an acute MI compared to a control group. Similarly, Inokubo et al. [29] documented MMP-9 levels in plasma obtained from the great cardiac vein in 29 patients with acute coronary syndromes. This study again demonstrated elevated MMP-9 levels following myocardial ischaemia. Both of these clinical studies concluded that the elevated MMP-9 levels were due to a process of active plaque rupture in the coronary circulation. The possibility exists however, that the raised MMP-9 concentration may be derived from ventricular tissue.

This prospect has been investigated in unpublished observations from our laboratory. Our group has quantified MMP-9 levels in a cohort of patients following acute anterior MI, who have echocardiographic and clinical follow up. The MMP-9 plasma concentrations showed an identical pattern to previous investigations [28,29] with a peak on days 2–3. Interestingly, peak MMP-9 levels correlated positively with N-terminal pro-brain natriuretic peptide, ventricular volume 6 weeks postinfarct and inversely with wall motion index score, a measure of left ventricular function. Based on previous observations with these parameters [30], it may be concluded that plasma levels of MMP-9 following MI may be predictive for ventricular remodelling.

Considerably more data will be required to establish the role of MMP expression in acute and chronic recovery from MI. However, if such a role is proven then the clinical implications are significant with regard to clinical trials of MMP inhibitors and the role of functional MMP polymorphisms [31] in recovery from MI. One potential area of immediate importance is the relationship between HMG CoA reductase inhibition and ventricular function. Experimental studies have recently demonstrated that fluvastatin inhibited MMP activity and improved ventricular ejection following acute MI [32].

	References

Top 1 Expression of MMPs... 2 Ventricular remodelling and... 3 Myocardial infarction and... 4 Clinical observations References

 

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