Abstract 12040: JAK-STAT Signalling and the Atrial Fibrillation-Promoting Fibrotic Substrate: Pathogenic Role and Possible Therapeutic Target
Introduction: Left atrial (LA) fibrosis is an important feature of the atrial fibrillation (AF) substrate. The JAK-STAT system, activated by platelet derived growth factor (PDGF), contributes to cardiac remodeling but its role in AF is unknown. Here, we investigated the participation of the JAK-STAT system in LA fibrosis development.
Methods: Heart failure (HF) was induced in dogs by ventricular tachypacing (VTP, 240 bpm) and in mice subjected to myocardial infarction (MI). Protein and mRNA expression were measured in freshly isolated LA fibroblasts (FBs) by Western blot and qPCR. Mice received S3I-201,a selective STAT3 inhibitor, or vehicle control (CTL) by osmotic minipump for 2 weeks post MI.
Results: HF dogs developed progressive LA-selective fibrosis and AF susceptibility beginning at 1 wk VTP. HF increased JAK2 mRNA expression in LA FBs from 1 wk VTP (1.4-1.5 fold**, **P<0.01). Phosphorylated JAK2 and STAT3 protein increased in HF atrial tissue by 2.5** and 2.9* fold (*p<0.05) respectively. Upstream signalling through PDGF was also enhanced by HF: PDGF A/C/D upregulated by 2.2-3.5*** fold (***p<0.001); PDGFR β upregulated by 2.3** fold. PDGF stimulation of CTL dog LA FBs increased TGFβ1, TGFβ receptor 2, STAT3, collagen 1α1 and collagen 3α1 expression (by 1.2-2.3 fold***). These effects were abolished by S3I-201 in a dose dependent manner (by 79%*** at 100 μM). In vivo S3I-201 treatment (Figure) decreased LA fibrosis (by 60%***), LA dimension at end systole (by 11%*) and P wave duration (by 31%***). MI-induced LV dilation and contractile dysfunction were not affected by S3I-201.
Conclusions: HF activates the LA JAK-STAT system via enhanced PDGF signalling. JAK-STAT inhibition reduces the profibrotic effects of PDGF stimulation on canine FBs in vitro and attenuates LA fibrosis and electrical remodeling post MI in mice. These results suggest that the JAK/STAT pathway plays an important role in LA fibrogenesis and is a potential target for LA fibrosis prevention in man.
Author Disclosures: Y. Chen: None. S. Surinkaew: None. X.Y. Qi: None. H. Huang: None. M.A. Gillis: None. F. Duval: None. Y.F. Shi: None. P. Naud: None. J.C. Tardif: None. D. Dobrev: None. S. Nattel: None.
- © 2015 by American Heart Association, Inc.