Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1, 2 and 9 in the human coronary artery
Introduction
Atherosclerotic luminal narrowing is determined by plaque mass and the mode of geometrical remodeling. Constrictive remodeling accelerates and expansive remodeling prevents luminal narrowing by plaque formation [1], [2], [3], [4], [5], [6]. In the acute phase luminal narrowing may be enhanced by plaque rupture and subsequent thrombus formation [7], [8], [9], [10]. Recently, we reported that in femoral artery segments the type of atherosclerotic remodeling is associated with the presence of histological markers for plaque vulnerability: more inflammatory cells but less collagen and smooth muscle cells were observed in the caps and shoulders of cross-sections that showed expansive enlargement compared with the more stable constrictively remodeled cross-sections [11]. The concept of this remodeling paradox, that expansive enlargement prevents luminal narrowing on one hand but may be associated with vulnerable plaques on the other hand, is supported by recently reported clinical ultrasound studies in which the mode of remodeling was found to be associated with the patients’ clinical syndrome [12], [13].
Vascular and inflammatory cells can modulate the structure and composition of the extracellular matrix by producing enzymes involved in its degradation. In vulnerable plaques matrix metalloproteinases (MMPs), that are secreted by macrophages, digest the matrix components within the fibrous cap. In cross-sections of atherosclerotic arteries revealing extreme expansive remodeling, like aneurysms, increased MMP activity within the arterial wall and a higher density of macrophages may be observed within the arterial wall [14]. Mainly the gelatinases MMP-2 and MMP-9 are highly expressed and more active in enlarged aneurysmatic arteries.
It remains to be investigated whether the increased prevalence of inflammatory cells in expansively remodeled segments compared with constrictively remodeled segments is also evident for the atherosclerotic coronary artery. In addition, it is unknown if such higher prevalence of macrophages in enlarged segments is also associated with an enhanced release of matrix metalloproteases that are thought to play a pivotal role in both matrix degradation and plaque destabilization [15], [16], [17], [18] and atherosclerotic remodeling [14], [19].The aim of the present study was to investigate the association between the mode of remodeling and the presence of macrophages and MMP-1, MMP-2 and MMP-9 in coronary atherosclerotic cross-sections. In addition, zymography was performed to study the gelatinase activity in atherosclerotic cross-sections that show expansive and constrictive remodeling.
Section snippets
Methods
Fourteen hearts were obtained within 24 h post-mortem (eight men and six women, 71±8 years) from patients who did not die of cardiovascular disease. The right coronary artery (RCA, n=13), left anterior descending coronary artery (LAD, n=12) and left circumflex (LCX, n=11) were dissected from the epicardium over a length of 5–10 cm from their origin. Six arteries were not used for analysis due to severe calcifications or extensive cutting artifact. The dissected coronary arteries were frozen in
Results
From 36 coronary arteries, 45 and 51 segments were selected with a vessel area that were found to be >10% smaller and larger compared with the adjacent segments, respectively (two to four segments/artery). Morphometric measurements of the cross-sections that demonstrated expansive or constrictive remodeling are depicted in Table 1. Lumen area, plaque area, IEL-area and EEL-area were all larger in the expansively remodeled cross-sections compared with the cross-sections classified in the
Discussion
The extracellular matrix plays a role in maintaining structural integrity of the arterial wall. The matrix remodels during the course of development, growth and wound healing. Comparable shifts in the synthesis/degradation balance occur in the pathogenesis of many diseases [21], [22]. MMPs are natural matrix degrading enzymes that are present in active as well as in inactive forms within the arterial wall. The role of MMPs in plaque destabilization is well recognized: MMPs are more prevalent
Conclusions
Expansive remodeling in atherosclerotic coronary artery segments is associated with more MMP-2 and MMP-9 in the plaque compared with constrictive remodeling. This association between remodeling mode and MMPs was evident for the plaque but not for the adventitia. Corrected for the amount of protein, more active MMP-2 was observed in plaques of expansively remodeled segments compared with constrictively remodeled segments. It might be postulated that MMPs in the plaque play a causal role not only
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