Molecular basis of selective atrial fibrosis due to overexpression of transforming growth factor-β1.

Abstract

AIMS:

Animal studies show that transforming growth factor-β1 (TGF-β1) is an important mediator of atrial fibrosis and atrial fibrillation (AF). This study investigated the role of TGF-β1 in human AF and the mechanism of atrial-selective fibrosis.

METHODS AND RESULTS:

Atrial specimens from 17 open heart surgery patients and left atrial and ventricular specimens from 17 explanted hearts were collected to assess the relationship between TGF-β1, AF, and differential atrial vs. ventricular TGF-β1 levels. A transgenic mouse model overexpressing active TGF-β1 was used to study the mechanisms underlying the resultant atrial-selective fibrosis. Higher right atrial total TGF-β1 levels (2.58 ± 0.16-fold, P < 0.0001) and active TGF-β1 (3.7 ± 0.7-fold, P = 0.013) were observed in those that developed post-operative AF. Although no ventricular differences were observed, 11 explanted heart failure hearts exhibited higher atrial TGF-β1 levels than 6 non-failing hearts (2.30 ± 0.87 fold higher, P < 0.001). In the transgenic mouse, TGF-β1 receptor-1 kinase blockade resulted in decreased atrial expression of fibrosis-related genes. By RNA microarray analyses in that model, 80 genes in the atria and only 2 genes in the ventricle were differentially expressed. Although these mice atria, but not the ventricles, exhibited increased expression of fibrosis-related genes and phosphorylation of Smad2, there were no differences in TGF-β1 receptor levels or Smads in the atria compared with the ventricles.

CONCLUSIONS:

TGF-β1 mediates selective atrial fibrosis in AF that occurs via TGF-β Receptor 1/2 and the classical Smad pathway. The differential atrial vs. ventricular fibrotic response occurs at the level of TGF-β1 receptor binding or phosphorylation.

• Authors: Dolkun Rahmutula, Gregory M Marcus, Emily E Wilson, Chun-Hua Ding, Yuanyuan Xiao, Agnes C Paquet, Rebecca Barbeau, Andrea J Barczak, David J Erle, Jeffrey E Olgin
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 99 Issue 4 Pg. 769-79 (Sep 01 2013) ISSN: 1755-3245 [Electronic] England
• PMID: 23612580 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Transforming Growth Factor beta
• Transforming Growth Factor beta1

Topics

• Animals
• Atrial Fibrillation (etiology)
• Fibrosis
• Heart Atria (pathology)
• Humans
• Mice
• Mice, Transgenic
• Mink
• Receptors, Transforming Growth Factor beta (analysis)
• Transforming Growth Factor beta1 (analysis, physiology)