Expression of fibromodulin in carotid atherosclerotic plaques is associated with diabetes and cerebrovascular events

Abstract

Expression of fibromodulin in carotid atherosclerotic plaques is associated with diabetes and cerebrovascular events.Shami, Annelie; Tengryd, Christoffer; Asciutto, Giuseppe; Bengtsson, Eva; Nilsson, Jan; Hultgårdh, Anna; Goncalves, Isabel Link to publication Citation for published version (APA): Shami, A., Tengryd, C., Asciutto, G., Bengtsson, E., Nilsson, J., Hultgårdh, A., & Goncalves, I. (2015). Expression of fibromodulin in carotid atherosclerotic plaques is associated with diabetes and cerebrovascular events. Atherosclerosis, 241(2), 701-708. DOI: 10.1016701-708. DOI: 10. /j.atherosclerosis.2015 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ABSTRACTAims The small leucine-rich proteoglycans fibromodulin and lumican are functionally related extracellular matrix proteins involved in the regulation of collagen fiber formation. Fibromodulin-deficient apolipoprotein E-null mice have decreased vascular retention of lipids and reduced development of atherosclerosis suggesting that fibromodulin may influence the disease process. The aim of the present study was to investigate if fibromodulin and lumican are expressed in human carotid plaques and to determine if their expression is associated with the occurrence of preoperative symptoms and with risk for postoperative cardiovascular events.Methods and Results 153 plaques (51% symptomatic) obtained by carotid endarterectomy were included in this study. Plaque content was analyzed by immunohistochemistry and plaque cytokine content by multiplex technology. Fibromodulin and lumican were widely expressed in plaques and fibromodulin expression was significantly higher in symptomatic plaques. Expression of fibromodulin was significantly higher in plaques obtained from patients with diabetes and a high fibromodulin expression was associated with a higher incidence of post-operative cerebrovascular events, whereas no such associations were seen for lumican. Fibromodulin expression also correlated with plaque lipids and several pro-inflammatory cytokines. In addition, fibromodulin expression correlated with low levels of smooth muscle cells and the antiinflammatory cytokine IL-10.Conclusions These observations support previous experimental findings in mice for a role of fibromodulin in atherosclerosis and provide clinical evidence of the involvement of fibromodulin in the inflammatory processes that characterize atherosclerotic plaque vulnerability. They also suggest that this is of particular importance in diabetes.

A role for proteoglycans in vascular disease

“…Fibromodulin and lumican are two KS-containing PGs that are found in human arteries and human atherosclerotic plaques (see review [6]). Both mRNA transcripts and core proteins of these KSPGs have been identified in vascular lesions, including diffuse intimal thickening, fatty streaks, complete atheroma with fibrous plaque and complicated lesions [6, 234, 235]. While there is considerable overlap in the distribution of these two PGs, it is of interest that lumican is deposited adjacent to lipid-filled macrophages in fibrolipid-filled lesions.…”

“…Fibromodulin also accumulates in atherosclerotic plaques and like lumican accumulates in macrophage-rich areas [234, 241]. Fibromodulin, like decorin, interacts with TGFβ1 and, when expressed in a vein graft failure organ culture model, fibromodulin caused a decrease in TGFβ1 and a reduction of neointimal hyperplasia of the vein graft [242].…”

CD90 Identifies Adventitial Mesenchymal Progenitor Cells in Adult Human Medium- and Large-Sized Arteries

“…Furthermore, an analysis to determine the key drivers of RGN 39 revealed that its top hierarchical key driver is CYTL1 —which is among the list of 120 CD90+ adventitial MSC genes of interest ( Figure 7 C). Moreover, several genes directly downstream of CYTL1 in RGN 39 have known connections to atherosclerosis or CAD, including MMP2 ( Liu et al., 2006 ), FMOD ( Fibromodulin ) ( Shami et al., 2015 ), CPNE4 ( Lee et al., 2015 ), and CD55 ( Leung et al., 2009 ) ( Figure 7 C). An additional key driver of RGN 39, ANOS1 , was also among our 120 CD90+ adventitial MSC genes of interest ( Figure 7 C).…”

Exploring the role of extracellular matrix proteins to develop biomarkers of plaque vulnerability and outcome

“…In ApoE‐deficient mice, the lack of fibromodulin has shown to reduce plaque formation . Furthermore, fibromodulin also showed to be associated with abnormal collagen fibres in the vulnerable plaque and decreased lipid retention in the vascular ECM .…”