PMID- 37200403
OWN - NLM
STAT- MEDLINE
DCOM- 20230906
LR  - 20230912
IS  - 1755-3245 (Electronic)
IS  - 0008-6363 (Print)
IS  - 0008-6363 (Linking)
VI  - 119
IP  - 11
DP  - 2023 Sep 5
TI  - Transforming growth factor-beta2 is associated with atherosclerotic plaque stability 
      and lower risk for cardiovascular events.
PG  - 2061-2073
LID - 10.1093/cvr/cvad079 [doi]
AB  - AIMS: Transforming growth factor-beta (TGF-beta) exists in three isoforms TGF-beta1, 
      -beta2, and -beta3. TGF-beta1 has been suggested to be important for maintaining plaque 
      stability, yet the role of TGF-beta2 and -beta3 in atherosclerosis remains to be 
      investigated.This study explores the association of the three isoforms of TGF-beta 
      with plaque stability in the human atherosclerotic disease. METHODS AND RESULTS: 
      TGF-beta1, -beta2, and -beta3 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-beta2 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-beta2 was the most abundant isoform and was increased 
      at both protein and mRNA levels in asymptomatic plaques. TGF-beta2 was the main 
      determinant separating asymptomatic plaques in an Orthogonal Projections to 
      Latent Structures Discriminant Analysis. TGF-beta2 correlated positively to features 
      of plaque stability and inversely to markers of plaque vulnerability. TGF-beta2 was 
      the only isoform inversely correlated to the matrix-degrading matrix 
      metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-beta2 
      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-beta2 levels had a lower risk to suffer from future CV events. CONCLUSIONS: 
      TGF-beta2 is the most abundant TGF-beta isoform in human plaques and may maintain 
      plaque stability by decreasing inflammation and matrix degradation.
CI  - (c) The Author(s) 2023. Published by Oxford University Press on behalf of the 
      European Society of Cardiology.
FAU - Edsfeldt, Andreas
AU  - Edsfeldt A
AUID- ORCID: 0000-0002-2691-9192
AD  - Department of Clinical Sciences, Malmo, Lund University, Lund, Sweden.
AD  - Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden.
AD  - Department of Cardiology, Skane University Hospital, Malmo, Sweden.
FAU - Singh, Pratibha
AU  - Singh P
AD  - Department of Clinical Sciences, Malmo, Lund University, Lund, Sweden.
FAU - Matthes, Frank
AU  - Matthes F
AUID- ORCID: 0000-0002-5115-8831
AD  - Department of Clinical Sciences, Malmo, Lund University, Lund, Sweden.
FAU - Tengryd, Christoffer
AU  - Tengryd C
AD  - Department of Clinical Sciences, Malmo, Lund University, Lund, Sweden.
FAU - Cavalera, Michele
AU  - Cavalera M
AD  - Department of Clinical Sciences, Malmo, Lund University, Lund, Sweden.
FAU - Bengtsson, Eva
AU  - Bengtsson E
AD  - Department of Clinical Sciences, Malmo, Lund University, Lund, Sweden.
AD  - Faculty of Health and Society, Malmo University, Malmo, Sweden.
AD  - Biofilms-Research Center for Biointerfaces, Malmo University, Malmo, Sweden.
FAU - Duner, Pontus
AU  - Duner P
AD  - Department of Clinical Sciences, Malmo, Lund University, Lund, Sweden.
FAU - Volkov, Petr
AU  - Volkov P
AD  - Department of Clinical Sciences, LUDC Bioinformatics Unit, Malmo, Lund 
      University, Lund, Sweden.
AD  - Data Science and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, 
      Gothenburg, Sweden.
FAU - Karadimou, Glykeria
AU  - Karadimou G
AD  - Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, 
      Sweden.
FAU - Gistera, Anton
AU  - Gistera A
AUID- ORCID: 0000-0002-4614-8030
AD  - Department of Medicine, Center for Molecular Medicine, Solna, Karolinska 
      University Hospital, Karolinska Institutet, Stockholm, Sweden.
FAU - Orho-Melander, Marju
AU  - Orho-Melander M
AUID- ORCID: 0000-0002-3578-2503
AD  - Department of Clinical Sciences, Malmo, Lund University, Lund, Sweden.
FAU - Nilsson, Jan
AU  - Nilsson J
AUID- ORCID: 0000-0002-9752-7479
AD  - Department of Clinical Sciences, Malmo, Lund University, Lund, Sweden.
FAU - Sun, Jiangming
AU  - Sun J
AD  - Department of Clinical Sciences, Malmo, Lund University, Lund, Sweden.
FAU - Goncalves, Isabel
AU  - Goncalves I
AUID- ORCID: 0000-0002-2935-0181
AD  - Department of Clinical Sciences, Malmo, Lund University, Lund, Sweden.
AD  - Department of Cardiology, Skane University Hospital, Malmo, Sweden.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (Transforming Growth Factor beta2)
RN  - 0 (Transforming Growth Factor beta1)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Protein Isoforms)
RN  - 0 (RNA, Messenger)
RN  - 76057-06-2 (Transforming Growth Factors)
SB  - IM
MH  - Humans
MH  - Transforming Growth Factor beta2/genetics
MH  - Transforming Growth Factor beta1
MH  - Matrix Metalloproteinase 9/genetics
MH  - *Plaque, Atherosclerotic
MH  - Constriction, Pathologic
MH  - Transforming Growth Factor beta/metabolism
MH  - Protein Isoforms
MH  - RNA, Messenger/genetics/metabolism
MH  - Inflammation/genetics
MH  - Transforming Growth Factors
MH  - *Cardiovascular Diseases
PMC - PMC10478752
OTO - NOTNLM
OT  - Atherosclerosis
OT  - Extracellular matrix
OT  - Inflammation
OT  - Plaque stability
OT  - TGF-beta
COIS- Conflict of interest: P.V. is now employed at Data Science and Quantitative 
      Biology, Discovery Sciences, R&D, AstraZeneca and M.C. is employed at GUBRA. The 
      remaining authors have nothing to disclose.
EDAT- 2023/05/18 19:12
MHDA- 2023/09/06 06:42
PMCR- 2023/05/18
CRDT- 2023/05/18 14:03
PHST- 2022/08/21 00:00 [received]
PHST- 2023/01/27 00:00 [revised]
PHST- 2023/02/21 00:00 [accepted]
PHST- 2023/09/06 06:42 [medline]
PHST- 2023/05/18 19:12 [pubmed]
PHST- 2023/05/18 14:03 [entrez]
PHST- 2023/05/18 00:00 [pmc-release]
AID - 7170345 [pii]
AID - cvad079 [pii]
AID - 10.1093/cvr/cvad079 [doi]
PST - ppublish
SO  - Cardiovasc Res. 2023 Sep 5;119(11):2061-2073. doi: 10.1093/cvr/cvad079.