Matrix Metalloproteinase 7 Is Associated with Symptomatic Lesions and Adverse Events in Patients with Carotid Atherosclerosis

Abstract

BackgroundAtherosclerosis is a major cause of cerebrovascular disease. Matrix metalloproteinases (MMPs) play an important role in matrix degradation within the atherosclerotic lesion leading to plaque destabilization and ischemic stroke. We hypothesized that MMP-7 could be involved in this process.MethodsPlasma levels of MMP-7 were measured in 182 consecutive patients with moderate (50–69%) or severe (≥70%) internal carotid artery stenosis, and in 23 healthy controls. The mRNA levels of MMP-7 were measured in atherosclerotic carotid plaques with different symptomatology, and based on its localization to macrophages, the in vitro regulation of MMP-7 in primary monocytes was examined.ResultsOur major findings were (i) Patients with carotid atherosclerosis had markedly increased plasma levels of MMP-7 compared to healthy controls, with particularly high levels in patients with recent symptoms (i.e., within the last 2 months). (ii) A similar pattern was found within carotid plaques with markedly higher mRNA levels of MMP-7 than in non-atherosclerotic vessels. Particularly high protein levels of MMP-7 levels were found in those with the most recent symptoms. (iii) Immunhistochemistry showed that MMP-7 was localized to macrophages, and in vitro studies in primary monocytes showed that the inflammatory cytokine tumor necrosis factor-α in combination with hypoxia and oxidized LDL markedly increased MMP-7 expression. (iv) During the follow-up of patients with carotid atherosclerosis, high plasma levels of MMP-7 were independently associated with total mortality.ConclusionOur findings suggest that MMP-7 could contribute to plaque instability in carotid atherosclerosis, potentially involving macrophage-related mechanisms.

Discovery of New Risk Markers for Ischemic Stroke Using a Novel Targeted Proteomics Chip

“…MMP-7 has been linked to human atherosclerosis 41 and to incident cardiovascular disease, 42 but this is the first study linking MMP-7 to incident ischemic stroke.…”

MicroRNA Let-7g and Atherosclerosis Plaque Stabilization

“…Johnson et al [32] showed that a specific MMP-12 inhibitor could retard the development of atherosclerosis and increase fibrosis within the plaque in an atherosclerotic mouse model. Also, it was found that patients with carotid atherosclerosis had markedly increased levels of MMP-7 in plasma, especially whom with newly diagnosed symptoms [33]. Silencing MMP-9 by RNA interference in the mice arteries had been shown to increase the thickness of the fibrous cap [34].…”

Multidimensional Contribution of Matrix Metalloproteinases to Atherosclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability

“…Localized production of MMP-7 by fully activated macrophages has been identified at the interface between the lipid core and fibrous cap, a divergence from the pattern of MMP-1, 3, and 9 secretion at plaque shoulders [70]. Proteolytic activity in this region may weaken apposition of the cap and predispose to plaque rupture, a scenario supported by the elevated MMP-7 plasma levels identified in patients with symptomatic carotid lesions [71]. Transcriptional activation of MMP-7 has been documented in hypoxic macrophages and the relevance of this physiologic adaptation to the regional production in atheromatous plaques remains to be determined [72]; however, a relationship to the initiation of angiogenesis ought to be considered.…”

“…Likewise, patients with plaques possessing elevated MMP-12 have a greater than 3-fold risk of stroke over the same timeframe [89]. Those with preoperative symptomatic carotid lesions have demonstrated elevated plasma levels of MMP-7 and associated increased all-cause mortality during an 8-year follow-up period, with this correlation being stronger than that between either age or increased CRP and mortality in this population [71]. Tracking the inflammatory biomarker CRP has repeatedly proven to be prognostic for stroke, however, and colocalization of MMP-10 with CRP in rupture-prone regions of carotid atherosclerotic plaques has led to the investigation of MMP-10 as a clinically relevant biomarker, particularly in patients with elevated CRP [67,68].…”