The proteoglycan mimecan is associated with carotid plaque vulnerability and increased risk of future cardiovascular death

Christoffer Tengryd,Signe Holm Nielsen,Michele Cavalera,Eva Bengtsson,Federica Genovese,Morten Karsdal,Pontus Dunér,Marju Orho-Melander,Jan Nilsson,Andreas Edsfeldt,Isabel Gonçalves

doi:10.1016/j.atherosclerosis.2020.09.011

Abstract

Background and aimsA vulnerable plaque is an atherosclerotic plaque that is rupture-prone with a higher risk to cause cardiovascular symptoms such as myocardial infarction or stroke. Mimecan or osteoglycin is a small leucine-rich proteoglycan, important for collagen fibrillogenesis, that has been implicated in atherosclerotic disease, yet the role of mimecan in human atherosclerotic disease remains unknown. Methods196 human atherosclerotic carotid plaques were immunostained for mimecan. Smooth muscle cells, macrophages and intraplaque haemorrhage were also measured with immunohistochemistry. Neutral lipids were stained with Oil Red O and calcium deposits were quantified. Plaque homogenate levels of MCP-1, IL-6 and MIP-1β were measured using a Proximity Extension Assay and MMP-9 levels were measured using Mesoscale. Glycosaminoglycans, collagen and elastin were assessed by colorimetric assays and TGF-β1, β2 and β3 were measured using a multiplex assay. Mimecan gene expression in THP-1 derived macrophages was quantified by qPCR and protein expression in vitro was visualized with immunofluorescence. Cardiovascular events were registered using medical charts and national registers during follow-up. ResultsMimecan correlated positively with plaque area of lipids, macrophages, intraplaque haemorrhage and inversely with smooth muscle cell staining. Mimecan also correlated positively with plaque levels of MMP-9 and MCP-1. Mimecan was upregulated in THP-1 derived macrophages upon stimulation with MCP-1. Patients with high levels of mimecan (above median) had higher risk for cardiovascular death. ConclusionsThis study indicates that mimecan is associated with a vulnerable plaque phenotype, possibly regulated by plaque inflammation. In line, plaque levels of mimecan independently predict future cardiovascular death.

Highlights

The rupture or erosion of an atherosclerotic plaque with subsequent thrombosis leads to myocardial infarction or stroke, which are the most common causes of death globally [1]
Mimecan correlated posi tively with plaque levels of MMP-9, one of the extracellular matrix degrading enzymes known to be associated with human plaque vulnerability (r = 0.288, p≤0.0001, Fig. 2A)
We showed that mimecan was associated with vulnerable plaque features including macrophages, neutral lipids, intraplaque haemorrhage and MMP-9

Summary

Introduction

The rupture or erosion of an atherosclerotic plaque with subsequent thrombosis leads to myocardial infarction or stroke, which are the most common causes of death globally [1]. A plaque that is prone to rupture, often called a vulnerable plaque, is characterized by a large lipid core, covered by a thin fibrous cap, with degraded extracellular matrix (ECM) proteins, poor in smooth muscle cells and rich in inflammatory infiltrates. A stable plaque has a smaller lipid core covered by a thick and less inflamed fibrous cap, rich in smooth muscle cells and collagen fibers [2,3]. The balance between the degradation and formation of ECM components is of great importance for plaque stability These processes are poorly understood in the context of human atherosclerosis. A vulnerable plaque is an atherosclerotic plaque that is rupture-prone with a higher risk to cause cardiovascular symptoms such as myocardial infarction or stroke. Results: Mimecan correlated positively with plaque area of lipids, macrophages, intraplaque haemorrhage and inversely with smooth muscle cell staining. Plaque levels of mimecan independently predict future cardiovascular death

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Results

Conclusion