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Osteomodulin Gene Expression Is Associated with Plaque Calcification, Stability, and Fewer Cardiovascular Events in the CPIP Cohort

Gonçalves, Isabel LU orcid ; Oduor, Loureen LU ; Matthes, Frank LU ; Rakem, Narjess LU ; Meryn, Jakob LU ; Skenteris, Nikolaos Taxiarchis ; Aspberg, Anders LU orcid ; Orho-Melander, Marju LU ; Nilsson, Jan LU and Matic, Ljubica , et al. (2022) In Stroke 53(3). p.79-84
Abstract

Background: Stable atherosclerotic plaques are characterized by thick fibrous caps of smooth muscle cells, collagen, and macrocalcifications. Identifying factors of plaque stability is necessary to design drugs to prevent plaque rupture and symptoms. Osteomodulin, originally identified in bones, is expressed by bone synthesizing osteoblasts and involved in mineralization. In the present study, we analyzed osteomodulin expression in human carotid plaques, its link with plaque phenotype, calcification, and future cardiovascular events. Methods: Osteomodulin gene expression (OMD; n=82) was determined by RNA sequencing and osteomodulin protein levels by immunohistochemistry (n=45) in carotid plaques obtained by endarterectomy from patients... (More)

Background: Stable atherosclerotic plaques are characterized by thick fibrous caps of smooth muscle cells, collagen, and macrocalcifications. Identifying factors of plaque stability is necessary to design drugs to prevent plaque rupture and symptoms. Osteomodulin, originally identified in bones, is expressed by bone synthesizing osteoblasts and involved in mineralization. In the present study, we analyzed osteomodulin expression in human carotid plaques, its link with plaque phenotype, calcification, and future cardiovascular events. Methods: Osteomodulin gene expression (OMD; n=82) was determined by RNA sequencing and osteomodulin protein levels by immunohistochemistry (n=45) in carotid plaques obtained by endarterectomy from patients with or without cerebrovascular symptoms from the CPIP (Carotid Plaque Imaging Project) cohort, Skåne University Hospital, Sweden. Plaque components were assessed by immunohistochemistry, RNA sequencing, and multiplex analysis. Patients were followed for cardiovascular events or cardiovascular death during a median of 57 or 70 months, respectively, using national registers. Results: OMD levels were increased in plaques from asymptomatic patients compared to symptomatics. High OMD levels were associated with fewer cardiovascular events during follow-up. OMD correlated positively with smooth muscle α-actin (ACTA2; r=0.73, P=10-13) and collagen (COL1A2; r=0.4, P=0.0002), but inversely with CD68 gene expression (r=-0.67, P=10-11), lipids (r=-0.37, P=0.001), intraplaque hemorrhage (r=-0.32, P=0.010), inflammatory cytokine, and matrix metalloproteinase plaque contents. OMD was positively associated with MSX2 (Msh Homeobox 2) (r=0.32, P=0.003), a marker of preosteoblast differentiation, BMP4 (bone morphogenetic protein) (r=0.50, P=0.000002) and BMP6 (r=0.47, P=0.000007), plaque calcification (r=0.35, P=0.016), and was strongly upregulated in osteogenically stimulated smooth muscle cells, which was further increased upon BMP stimulation. Osteomodulin protein was present in calcified regions. Osteomodulin protein levels were associated with plaque calcification (r=0.41, P=0.006) and increased in macrocalcified plaques. Conclusions: These data show that osteomodulin mRNA and protein levels are associated with plaque calcification in human atherosclerosis. Furthermore, osteomodulin mRNA, but not protein levels, is associated with plaque stability.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
atherosclerosis, gene expression, immunohistochemistry, osteomodulin, plaques, atherosclerotic
in
Stroke
volume
53
issue
3
pages
79 - 84
publisher
American Heart Association
external identifiers
  • pmid:35135320
  • scopus:85125554222
ISSN
0039-2499
DOI
10.1161/STROKEAHA.121.037223
language
English
LU publication?
yes
additional info
Funding Information: This work was funded by grants from Swedish Heart and Lung foundation, Albert Påhlsson Foundation, Crafoord Foundation, funding from the Swedish Research Council (Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15-0067) to the Lund University Diabetes Center, Swedish Society for Medical Research, Emil and Wera Cornell foundation, Swedish Research Council, Swedish Society of Medicine, SUS foundations and funds, Åke Wiberg Foundation, Knut and Alice Wallenberg foundation, Medical Faculty at Lund University and Region Skåne. Funding Information: This work was funded by grants from Swedish Heart and Lung foundation, Albert P?hlsson Foundation, Crafoord Foundation, funding from the Swedish Research Council (Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15-0067) to the Lund University Diabetes Center, Swedish Society for Medical Research, Emil and Wera Cornell foundation, Swedish Research Council, Swedish Society of Medicine, SUS foundations and funds, ?ke Wiberg Foundation, Knut and Alice Wallenberg foundation, Medical Faculty at Lund University and Region Sk?ne. Publisher Copyright: © 2022 Lippincott Williams and Wilkins. All rights reserved.
id
a913c81d-d1d3-4f65-bd5e-51aef42e0fbc
date added to LUP
2022-03-22 11:12:31
date last changed
2022-07-28 07:38:58
@article{a913c81d-d1d3-4f65-bd5e-51aef42e0fbc,
  abstract     = {{<p>Background: Stable atherosclerotic plaques are characterized by thick fibrous caps of smooth muscle cells, collagen, and macrocalcifications. Identifying factors of plaque stability is necessary to design drugs to prevent plaque rupture and symptoms. Osteomodulin, originally identified in bones, is expressed by bone synthesizing osteoblasts and involved in mineralization. In the present study, we analyzed osteomodulin expression in human carotid plaques, its link with plaque phenotype, calcification, and future cardiovascular events. Methods: Osteomodulin gene expression (OMD; n=82) was determined by RNA sequencing and osteomodulin protein levels by immunohistochemistry (n=45) in carotid plaques obtained by endarterectomy from patients with or without cerebrovascular symptoms from the CPIP (Carotid Plaque Imaging Project) cohort, Skåne University Hospital, Sweden. Plaque components were assessed by immunohistochemistry, RNA sequencing, and multiplex analysis. Patients were followed for cardiovascular events or cardiovascular death during a median of 57 or 70 months, respectively, using national registers. Results: OMD levels were increased in plaques from asymptomatic patients compared to symptomatics. High OMD levels were associated with fewer cardiovascular events during follow-up. OMD correlated positively with smooth muscle α-actin (ACTA2; r=0.73, P=10<sup>-13</sup>) and collagen (COL1A2; r=0.4, P=0.0002), but inversely with CD68 gene expression (r=-0.67, P=10<sup>-11</sup>), lipids (r=-0.37, P=0.001), intraplaque hemorrhage (r=-0.32, P=0.010), inflammatory cytokine, and matrix metalloproteinase plaque contents. OMD was positively associated with MSX2 (Msh Homeobox 2) (r=0.32, P=0.003), a marker of preosteoblast differentiation, BMP4 (bone morphogenetic protein) (r=0.50, P=0.000002) and BMP6 (r=0.47, P=0.000007), plaque calcification (r=0.35, P=0.016), and was strongly upregulated in osteogenically stimulated smooth muscle cells, which was further increased upon BMP stimulation. Osteomodulin protein was present in calcified regions. Osteomodulin protein levels were associated with plaque calcification (r=0.41, P=0.006) and increased in macrocalcified plaques. Conclusions: These data show that osteomodulin mRNA and protein levels are associated with plaque calcification in human atherosclerosis. Furthermore, osteomodulin mRNA, but not protein levels, is associated with plaque stability.</p>}},
  author       = {{Gonçalves, Isabel and Oduor, Loureen and Matthes, Frank and Rakem, Narjess and Meryn, Jakob and Skenteris, Nikolaos Taxiarchis and Aspberg, Anders and Orho-Melander, Marju and Nilsson, Jan and Matic, Ljubica and Edsfeldt, Andreas and Sun, Jiangming and Bengtsson, Eva}},
  issn         = {{0039-2499}},
  keywords     = {{atherosclerosis; gene expression; immunohistochemistry; osteomodulin; plaques, atherosclerotic}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  pages        = {{79--84}},
  publisher    = {{American Heart Association}},
  series       = {{Stroke}},
  title        = {{Osteomodulin Gene Expression Is Associated with Plaque Calcification, Stability, and Fewer Cardiovascular Events in the CPIP Cohort}},
  url          = {{http://dx.doi.org/10.1161/STROKEAHA.121.037223}},
  doi          = {{10.1161/STROKEAHA.121.037223}},
  volume       = {{53}},
  year         = {{2022}},
}