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Transforming growth factor-β2 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events

Edsfeldt, Andreas LU ; Singh, Pratibha LU ; Matthes, Frank LU ; Tengryd, Christoffer LU ; Cavalera, Michele LU ; Bengtsson, Eva LU orcid ; Dunér, Pontus LU ; Volkov, Petr LU ; Karadimou, Glykeria and Gisterå, Anton , et al. (2023) In Cardiovascular Research 119(11). p.2061-2073
Abstract

Aims: Transforming growth factor-beta (TGF-β) exists in three isoforms TGF-β1, -β2, and -β3. TGF-β1 has been suggested to be important for maintaining plaque stability, yet the role of TGF-β2 and -β3 in atherosclerosis remains to be investigated. This study explores the association of the three isoforms of TGF-β with plaque stability in the human atherosclerotic disease. Methods and results: TGF-β1, -β2, and -β3 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis >70% or without symptoms and >80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and... (More)

Aims: Transforming growth factor-beta (TGF-β) exists in three isoforms TGF-β1, -β2, and -β3. TGF-β1 has been suggested to be important for maintaining plaque stability, yet the role of TGF-β2 and -β3 in atherosclerosis remains to be investigated. This study explores the association of the three isoforms of TGF-β with plaque stability in the human atherosclerotic disease. Methods and results: TGF-β1, -β2, and -β3 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis >70% or without symptoms and >80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and biochemically. Matrix metalloproteinases and monocyte chemoattractant protein-1 (MCP-1) was measured with immunoassays. The effect of TGF-β2 on inflammation and protease activity was investigated in vitro using THP-1 and RAW264.7 macrophages. Patients were followed longitudinally for cardiovascular (CV) events. TGF-β2 was the most abundant isoform and was increased at both protein and mRNA levels in asymptomatic plaques. TGF-β2 was the main determinant separating asymptomatic plaques in an Orthogonal Projections to Latent Structures Discriminant Analysis. TGF-β2 correlated positively to features of plaque stability and inversely to markers of plaque vulnerability. TGF-β2 was the only isoform inversely correlated to the matrix-degrading matrix metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-β2 pre-treatment reduced MCP-1 gene and protein levels as well as matrix metalloproteinase-9 gene levels and activity. Patients with plaques with high TGF-β2 levels had a lower risk to suffer from future CV events. Conclusions: TGF-β2 is the most abundant TGF-β isoform in human plaques and may maintain plaque stability by decreasing inflammation and matrix degradation.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Atherosclerosis, Extracellular matrix, Inflammation, Plaque stability, TGF-β
in
Cardiovascular Research
volume
119
issue
11
pages
2061 - 2073
publisher
Oxford University Press
external identifiers
  • pmid:37200403
  • scopus:85165720853
ISSN
0008-6363
DOI
10.1093/cvr/cvad079
language
English
LU publication?
yes
additional info
Funding Information: This work was supported by Swedish Research Council; Swedish Heart and Lung Foundation; Skåne University Hospital; Påhlsson Foundation; Crafoord Foundation; Swedish Society for Medical Research; Swedish Society of Medicine; Lund University Diabetes Centre; Swedish Foundation for Strategic Research Dnr IRC15-0067, and Sparbank Färs and Frosta Foundation. The Knut and Alice Wallenberg Foundation, the Medical Faculty of Lund University, and Region Skåne are acknowledged for their generous financial support. Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.
id
60224c29-92db-4afc-8b2d-9ce7759f4c29
date added to LUP
2023-11-03 15:56:37
date last changed
2024-04-19 03:34:27
@article{60224c29-92db-4afc-8b2d-9ce7759f4c29,
  abstract     = {{<p>Aims: Transforming growth factor-beta (TGF-β) exists in three isoforms TGF-β1, -β2, and -β3. TGF-β1 has been suggested to be important for maintaining plaque stability, yet the role of TGF-β2 and -β3 in atherosclerosis remains to be investigated. This study explores the association of the three isoforms of TGF-β with plaque stability in the human atherosclerotic disease. Methods and results: TGF-β1, -β2, and -β3 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis &gt;70% or without symptoms and &gt;80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and biochemically. Matrix metalloproteinases and monocyte chemoattractant protein-1 (MCP-1) was measured with immunoassays. The effect of TGF-β2 on inflammation and protease activity was investigated in vitro using THP-1 and RAW264.7 macrophages. Patients were followed longitudinally for cardiovascular (CV) events. TGF-β2 was the most abundant isoform and was increased at both protein and mRNA levels in asymptomatic plaques. TGF-β2 was the main determinant separating asymptomatic plaques in an Orthogonal Projections to Latent Structures Discriminant Analysis. TGF-β2 correlated positively to features of plaque stability and inversely to markers of plaque vulnerability. TGF-β2 was the only isoform inversely correlated to the matrix-degrading matrix metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-β2 pre-treatment reduced MCP-1 gene and protein levels as well as matrix metalloproteinase-9 gene levels and activity. Patients with plaques with high TGF-β2 levels had a lower risk to suffer from future CV events. Conclusions: TGF-β2 is the most abundant TGF-β isoform in human plaques and may maintain plaque stability by decreasing inflammation and matrix degradation.</p>}},
  author       = {{Edsfeldt, Andreas and Singh, Pratibha and Matthes, Frank and Tengryd, Christoffer and Cavalera, Michele and Bengtsson, Eva and Dunér, Pontus and Volkov, Petr and Karadimou, Glykeria and Gisterå, Anton and Orho-Melander, Marju and Nilsson, Jan and Sun, Jiangming and Gonçalves, Isabel}},
  issn         = {{0008-6363}},
  keywords     = {{Atherosclerosis; Extracellular matrix; Inflammation; Plaque stability; TGF-β}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{2061--2073}},
  publisher    = {{Oxford University Press}},
  series       = {{Cardiovascular Research}},
  title        = {{Transforming growth factor-β2 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events}},
  url          = {{http://dx.doi.org/10.1093/cvr/cvad079}},
  doi          = {{10.1093/cvr/cvad079}},
  volume       = {{119}},
  year         = {{2023}},
}