Transforming growth factor-β2 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events
(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.
(Less)
- author
- organization
-
- Cardiovascular Research - Translational Studies (research group)
- EXODIAB: Excellence of Diabetes Research in Sweden
- WCMM-Wallenberg Centre for Molecular Medicine
- Vascular Biology (research group)
- Division of Microbiology, Immunology and Glycobiology - MIG
- Cardiovascular Research - Matrix and Inflammation in Atherosclerosis (research group)
- Cardiovascular Research - Immunity and Atherosclerosis (research group)
- Diabetic Complications (research group)
- Diabetes - Cardiovascular Disease (research group)
- EpiHealth: Epidemiology for Health
- publishing date
- 2023-08
- 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
- 2025-02-08 09:18:02
@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 >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.</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}}, }