Abstract
Background and Purpose: Polymorphisms and serum levels of Matrix Metalloproteinases (MMP) and Tissue Inhibitor of Metalloproteinases (TIMP) have been studied with regard to atheromatous plaques and ischemic stroke, while no studies of DNA methylation (DNAm) patterns of MMP or TIMP have been performed to that end. Here, we evaluate DNAm levels of the MMP and TIMP gene families in human carotid plaques and blood samples of atherothrombotic stroke patients.Methods: We profiled the DNAm status of stable and ulcerated atherosclerotic plaques obtained as pair sets from three patients who underwent carotid endarterectomy surgery. We selected 415 CpG sites, mapping into MMPs and TIMPs genes for further study. Secondly, the statistically associated CpG sites were analyzed in blood samples from two separate atherothrombotic stroke cohorts (total sample size = 307), ischemic stroke-cohort 1 (ISC-1): 37 atherothrombotic patients and 6 controls, ischemic stroke-cohort 2 (ISC-2): 80 atherothrombotic patients and 184 controls. DNAm levels from plaque tissue and blood samples were evaluated using a high-density microarray Infinium, HumanMethylation450 BeadChip and Infinium MethylationEPIC BeadChip.Results: Three CpG sites were statistically significantly associated with unstable plaque portions; cg02969624, q-value = 0.035 (TIMP2), and cg04316754, q-value = 0.037 (MMP24) were hypermethylated, while cg24211657 q-value = 0.035 (TIMP2) was hypomethylated. Association of cg04316754 (MMP24) methylation levels with atherothrombotic risk was also observed in blood tissue: ISC-1 p-values = 0.03, ISC-2 p-value = 1.9 × 10-04.Conclusions: The results suggest different DNAm status of MMP24 between stable and unstable atherothrombotic carotid plaques, and between atherothrombotic stroke and controls in blood samples.
Highlights
Arteriosclerosis is the underlying pathology in most cases of cardiovascular disease (CVD), including ischemic stroke (IS), contributing to major mortality in Western countries
Association of cg04316754 (MMP24) methylation levels with atherothrombotic risk was observed in blood tissue: ischemic stroke-cohort 1 (ISC-1) p-values = 0.03, ISC2 p-value = 1.9 × 10-04
All CpG sites (CpGs) were interrogated in two independent blood sample ischemic stroke cohorts of atherothrombotic stroke subtype (TOAST classification), 415 CpGs in ISC-1 and 355 CpGs in ischemic stroke-cohort 2 (ISC-2) (Supplementary Table 3)
Summary
Arteriosclerosis is the underlying pathology in most cases of cardiovascular disease (CVD), including ischemic stroke (IS), contributing to major mortality in Western countries. Atherosclerosis is a process that involves a complex interaction between different factors and cell types, including cells of the vessel wall and immune system. During their formation, atherosclerotic lesions undergo different stages, starting from inflammatory endothelial activation/dysfunction and resulting in plaque vulnerability and rupture [1]. MMPs and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs), are involved in many processes, including wound healing, angiogenesis, inflammation, and bloodbrain barrier disruption [2, 3]. Polymorphisms and serum levels of Matrix Metalloproteinases (MMP) and Tissue Inhibitor of Metalloproteinases (TIMP) have been studied with regard to atheromatous plaques and ischemic stroke, while no studies of DNA methylation (DNAm) patterns of MMP or TIMP have been performed to that end. We evaluate DNAm levels of the MMP and TIMP gene families in human carotid plaques and blood samples of atherothrombotic stroke patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
