| First Author | Rahmutula D | Year | 2013 |
| Journal | Cardiovasc Res | Volume | 99 |
| Issue | 4 | Pages | 769-79 |
| PubMed ID | 23612580 | Mgi Jnum | J:258829 |
| Mgi Id | MGI:6141293 | Doi | 10.1093/cvr/cvt074 |
| Citation | Rahmutula D, et al. (2013) Molecular basis of selective atrial fibrosis due to overexpression of transforming growth factor-beta1. Cardiovasc Res 99(4):769-79 |
| abstractText | AIMS: Animal studies show that transforming growth factor-beta1 (TGF-beta1) is an important mediator of atrial fibrosis and atrial fibrillation (AF). This study investigated the role of TGF-beta1 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-beta1, AF, and differential atrial vs. ventricular TGF-beta1 levels. A transgenic mouse model overexpressing active TGF-beta1 was used to study the mechanisms underlying the resultant atrial-selective fibrosis. Higher right atrial total TGF-beta1 levels (2.58 +/- 0.16-fold, P < 0.0001) and active TGF-beta1 (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-beta1 levels than 6 non-failing hearts (2.30 +/- 0.87 fold higher, P < 0.001). In the transgenic mouse, TGF-beta1 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-beta1 receptor levels or Smads in the atria compared with the ventricles. CONCLUSIONS: TGF-beta1 mediates selective atrial fibrosis in AF that occurs via TGF-beta Receptor 1/2 and the classical Smad pathway. The differential atrial vs. ventricular fibrotic response occurs at the level of TGF-beta1 receptor binding or phosphorylation. |
