COMMENTARIES

The Association of Leukotriene Signaling with Matrix Metalloproteinase (MMP) Activity in Atherosclerotic Plaque Vulnerability and In-stent Restenosis

Magnus Bäck1,2, and Daniel Ketelhuth2, 1Department of Cardiology and 2Center for Molecular Medicine, Karolinska University Hospital, L8:03, 17176 Stockholm, Sweden, Email: Magnus.Back@ki.se ; Daniel.Ketelhuth@ki.se

The inflammatory activity and extracellular matrix (ECM) composition of an atherosclerotic lesion may represent a better evaluation of plaque vulnerability than radiographic and echographic determinations of coronary or carotid artery lumen occlusions. For example, pro-inflammatory signaling induced by leukotrienes, and the ECM-degrading enzyme family of matrix metalloproteinases (MMPs) have individually been associated with atherosclerotic plaque instability [1,2]. In addition, recent findings indicate that these two pathways are intimately linked, with implications not only for inflammation-induced plaque rupture, but also in abdominal aortic aneurysms (AAA) [3] and the response to percutaneous interventions of stenotic or occluded vessels [4].

The synthesis of leukotrienes takes place locally within the atherosclerotic lesion through the 5-lipoxygenase pathway of arachidonic acid metabolism [5]. Inhibition of the leukotriene pathway induces beneficial effects in animal models of atherosclerosis [6] and intimal hyperplasia [7]. Genetic association studies have in addition shown that certain polymorphisms within the genes encoding the enzymes involved in leukotriene biosynthesis correlate not only with subclinical atherosclerosis but also with an increased risk of myocardial infarction and stroke [8], suggesting a link between the leukotriene pathway and plaque rupture. 

The MMP family consists of 28 zinc-containing endopeptidases involved in the metabolism of ECM proteins, such as collagen, elastin, gelatins, casein, etc. In addition, MMPs also exert proteolytic activity against non-matrix proteins, such as cytokines, chemokines, and growth factors [9]. The proteinase activities exerted by 11 of the 28 MMPs have been implicated in some of the biological processes associated with atherosclerosis and its ischemic clinical manifestations such as myocardial infarction and stroke.

The production, secretion, and activation of MMPs may be dependent on the generation of endogenous leukotrienes, as suggested by the co-localization of 5-lipoxygenase with MMPs in human carotid atherosclerotic lesions [10]. The latter observation was recently extended to endarterectomies derived from diabetic patients, in which 5-lipoxygenase expression and leukotriene B4 production was associated with increased levels of MMP proteins [11]. Furthermore, smokers exhibit a significant correlation between leukotriene B4 concentrations and MMP-9 activity in saliva [12] (see Figure below). Taken together, those studies suggest that both leukotrienes and MMPs are simultaneously increased during an inflammatory response.

In hypercholesterolemic rabbits subjected to vascular injury, MMPs have a cell-specific expression pattern, with SMCs as major source of MMP-2 whereas MMP-9 activity can be correlated to lesion macrophage content [4]. When the vascular balloon injury is followed by stent implantation in the carotid artery of hypercholesterolemic rabbits, a model closely resembling percutaneous coronary interventions (PCI) can be obtained. Using the latter protocol, oral treatment with a leukotriene receptor antagonist was recently shown to inhibit the in-stent intimal hyperplasia [4]. Interestingly also MMP-2 and MMP-9 activities in the lesions was reduced by the leukotriene receptor antagonist, as measured by zymography [4].

Several mechanisms can be suggested for a leukotriene/MMP interaction. In addition to MMP production by the structural components of the vascular wall, e.g. endothelial and smooth muscle cells, the infiltration of inflammatory cells into the atherosclerotic lesion results in a major increase of MMP activity. Since leukotrienes are potent leukocyte chemoattractants, it is interesting that the MMP-9 activities in lesions were significantly correlated to the degree of inhibition of macrophage infiltration induced by the leukotriene receptor antagonist in the abovementioned rabbit model [4].

Another important molecule recently related in the modulation of MMP-9 activity is the neutrophil gelatinase-associated lipocalin (NGAL). It has for example been shown that NGAL levels are increased in proportion to the increase of proteolytic activity of MMP-9 in the intima of injured vessels and that NGAL produced by smooth muscle cells can interact with MMP-9 and increase MMP-9 proteolytic activity [13]. Interestingly, the concentrations of MMP-9/NGAL complexes released from human AAA are significantly correlated to the leukotriene release [3] (see Figure below).

In addition to indirect effects on MMP activities through the recruitment of MMP-expressing macrophages and granulocytes, there is also in vitro evidence of direct effects of leukotrienes on MMP activity. For example, incubation of either human vessels or vascular smooth muscle cells in the presence of leukotriene B4 increases MMP-2 production [4,14]. Furthermore, inhibiting MMP activity in vascular smooth muscle cells through transfection with a siRNA against MMP-2 significantly inhibits their migration in response to leukotriene B4 [4].

In summary, the associations of the leukotriene signaling with atherosclerotic plaque vulnerability and in-stent restenosis may, at least in part, be mediated through the MMP pathway. The MMP-induced reduction of collagen and other ECM in the fibrous cap surrounding the atherosclerotic plaque may render the plaque more prone to rupture. Furthermore, leukotriene-induced MMP activity may also enhance the response to vascular injury since ECM degradation enables a path for cells to migrate.


References

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