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

Cardiovasc Res. 2023 Sep 5;119(11):2061-2073. doi: 10.1093/cvr/cvad079.


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.

Keywords: Atherosclerosis; Extracellular matrix; Inflammation; Plaque stability; TGF-β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiovascular Diseases*
  • Constriction, Pathologic
  • Humans
  • Inflammation / genetics
  • Matrix Metalloproteinase 9 / genetics
  • Plaque, Atherosclerotic*
  • Protein Isoforms
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta2 / genetics
  • Transforming Growth Factors


  • Transforming Growth Factor beta2
  • Transforming Growth Factor beta1
  • Matrix Metalloproteinase 9
  • Transforming Growth Factor beta
  • Protein Isoforms
  • RNA, Messenger
  • Transforming Growth Factors