Transforming growth factor-β2 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events
Andreas Edsfeldt, Pratibha Singh, Frank Matthes, Christoffer Tengryd, Michele Cavalera, Eva Bengtsson, Pontus Dunér, Petr Volkov, Glykeria Karadimou, Anton Gisterå, Marju Orho‐Melander, Jan Nilsson, Jiangming Sun, Isabel Gonçalves
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 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.