JAK-STAT signalling and the atrial fibrillation promoting fibrotic substrate.
OBJECTIVE
Left-atrial (LA) fibrosis is an important feature of many atrial fibrillation (AF) substrates. The JAK-STAT system contributes to cardiac remodelling, but its role in AF is unknown. Here we investigated JAK-STAT changes in an AF-model and their potential contributions to LA-fibrosis.


RESULTS
LA-remodelling was studied in dogs with heart failure (HF) induced by ventricular tachypacing (VTP, 240 bpm), and in mice with left-ventricular (LV) dysfunction due to myocardial infarction (MI). The selective STAT-3 inhibitor S3I-201 was administered to fibroblasts in vitro or mice in vivo (10 mg/kg/d, osmotic mini-pump). HF-dogs developed LA-selective fibrosis and AF-susceptibility at 1-week VTP. The mRNA-expression of platelet-derived growth factor (PDGF, a JAK-STAT activator) isoforms A, C and D, as well as JAK2, increased in LA fibroblasts from 1-week VTP. HF upregulated protein-expression of PDGF-receptor-β and phosphorylated (activated) signal transducer and activator of transcription 3 (STAT3) in LA. PDGF-AB stimulation of LA fibroblasts increased PDGFR-α, STAT3 and phosphorylated-STAT3 expression, as well as collagen-1 and fibronectin-1 protein secretion (by 1.6- to 20-fold), with smaller changes in LV fibroblasts. Phosphorylated-STAT3 and collagen upregulation were suppressed by the JAK2 inhibitor AG-490, PDGF receptor inhibitor AG1296 and STAT3-inhibitor SI3-201. In vivo S3I-201 treatment of MI-mice attenuated LA-fibrosis, LA-dilation and P-wave duration changes versus vehicle-control.


CONCLUSIONS
HF activates the LA JAK-STAT system and enhances PDGF-signalling. JAK-STAT inhibition reduces the profibrotic effects of PDGF stimulation on canine fibroblasts in vitro while attenuating in vivo LA-fibrosis and remodelling in post-MI mice, suggesting that the JAK/STAT pathway contributes to LA-fibrogenesis and might be a potential target for LA-fibrosis prevention.
Department of Medicine and Research Center Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, H1T 1C8 Canada.|Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6 Canada.
Yu
Y
Chen
Department of Medicine and Research Center Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, H1T 1C8 Canada.
Sirirat
S
Surinkaew
Department of Medicine and Research Center Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, H1T 1C8 Canada.
Patrice
P
Naud
Department of Medicine and Research Center Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, H1T 1C8 Canada.
Xiao-Yan
XY
Qi
Department of Medicine and Research Center Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, H1T 1C8 Canada.
Marc-Antoine
MA
Gillis
Department of Medicine and Research Center Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, H1T 1C8 Canada.
Yan-Fen
YF
Shi
Department of Medicine and Research Center Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, H1T 1C8 Canada.
Jean-Claude
JC
Tardif
Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Hufelandstrasse 55, Essen 45122, Germany.
Dobromir
D
Dobrev
Department of Medicine and Research Center Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, H1T 1C8 Canada.|Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6 Canada.|Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Hufelandstrasse 55, Essen 45122, Germany.
Stanley
S
Nattel