Abstract
Several large-scale genome-wide association studies have identified single-nucleotide polymorphisms in the genomic region of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats (ADAMTS)-7 and associations to coronary artery disease. Experimental studies have provided evidence for a functional role of ADAMTS-7 in both injury-induced vascular neointima formation and development of atherosclerotic lesions. However, whether ADAMTS-7 is associated with a specific plaque phenotype in humans has not been investigated. Carotid plaques (n = 206) from patients with and without cerebrovascular symptoms were analyzed for expression of ADAMTS-7 by immunohistochemistry and correlated to components associated with plaque vulnerability. Plaques from symptomatic patients showed increased levels of ADAMTS-7 compared with lesions from asymptomatic patients. High levels of ADAMTS-7 correlated with high levels of CD68-staining and lipid content, but with low smooth muscle cell and collagen content, which together are characteristics of a vulnerable plaque phenotype. ADAMTS-7 levels above median were associated with increased risk for postoperative cardiovascular events. Our data show that ADAMTS-7 is associated with a vulnerable plaque phenotype in human carotid lesions. These data support previous observations of a potential proatherogenic role of ADAMTS-7.
Highlights
Several large-scale genome-wide association studies (GWAS) have identified SNPs in the genomic region of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats (ADAMTS)-7 and associations to coronary artery disease (CAD)[1,2,3]
And Metalloproteinase with ThromboSpondin type repeats (ADAMTS)-7 displayed a negative correlation to MMP2, which has been associated with a more stable plaque phenotype[16], as well as to Matrix metalloproteinase (MMP)-3, whereas a positive association was seen to MMP-9 (Table 2)
Our data show that ADAMTS-7 in human atherosclerotic lesions is associated with a more vulnerable plaque phenotype (Fig. 1b), being positively associated with CD68-staining and lipids, but negatively associated with smooth muscle cell (SMC) and collagen (Table 2)
Summary
Several large-scale genome-wide association studies (GWAS) have identified SNPs in the genomic region of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats (ADAMTS)-7 and associations to coronary artery disease (CAD)[1,2,3]. Previous studies have focused on the role of ADAMTS-7 in cartilage degradation, and recently ADAMTS-7 was shown to enhance both osteoarthritis and collagen-induced arthritis in mice[5, 6]. The role of ADAMTS-7 in neointima formation is mediated via increased smooth muscle cell (SMC) migration by degradation of COMP and via impaired re-endothelialization[7, 9]. In addition to its role in restenosis, a recent study showed that ADAMTS-7-deficiency significantly reduces atherosclerotic lesion formation in both ApoE−/− and LDLr−/−mice[8]. In this study we analyzed ADAMTS-7 levels in 206 human carotid plaques and its association with components that affect plaque stability. High ADAMTS-7 levels were associated with an increased risk for postoperative cardiovascular (CV) events
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