Abstract 13789: Potential Role of PDGF-Activated JAK/STAT Pathway in CHF-Related Atrial-Selective Fibrotic Remodeling
Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia and its mechanisms are poorly understood. Platelet derived growth factor (PDGF) contributes to myofibroblast differentiation and activates JAK/STAT signaling. Here, we assessed how the PDGF-JAK/STAT pathway regulates atrial selective fibrosis in congestive heart failure (CHF).
Methods: CHF was induced in dogs by ventricular tachypacing (VTP, 240 bpm) for 0 (CTL), 12, 24 hrs; 1, and 2 wks (n=5-12/group). Fibroblasts (FBs) and cardiomyocytes (CMs) were freshly isolated from LA and LV of each dog. mRNA expression was assessed by qPCR. FBs from normal dogs were cultured and treated with PDGF-AB. PDGF receptor (PDGFR) protein was quantified by Western Blot.
Results: Dogs developed progressive CHF-related hemodynamic changes, atrial-selective fibrosis and AF susceptibility. PDGFA/C/D and JAK2 mRNA expression increased in LA FBs (~1.5-3.5-fold***), beginning at 1-wk VTP, while no changes were observed in LV. PDGFR mRNA was dominantly expressed in FBs versus CMs (by ~ 4.6-20.6-fold***). PDGFRα protein expression was greater in LA versus LV (by ~4.0-5.6-fold***). PDGFR-β, p-JAK2 and total-JAK2 were up-regulated in LA at 2 wk VTP (by ~2.3-2.7-fold**) but unchanged in LV. p-STAT3 and total-STAT3 were increased in both chambers in CHF (by ~ 1.6-2.9-fold**) while p-STAT3/t-STAT3 ratio only increased in LA (by ~1.9-fold*). After PDGF-AB stimulation in isolated FBs (1) PDGFR-α mRNA and protein were increased in LA (by ~1.9-3.1-fold***), with smaller changes in LV; (2) STAT3 expression and p-STAT3/STAT3 ratio were enhanced (LA-selective, by ~1.6-4.9-fold***) and the increase of p-STAT3 protein level was abolished by STAT3 inhibitor SI3-201 (by ~39%* versus PDGF-stimulation); (3) collagen secretion was enhanced (by ~1.2-fold* in LA), with smaller, nonsignificant changes in LV; (4) miR-133a mRNA expression was decreased (by ~42%-82%***), and its predicted target JAK2 was increased in both LA and LV (by ~1.2-1.3-fold*).
Conclusions: 1) CHF activates the PDGF-JAK/STAT pathway; 2) JAK/STAT enhancement is selective for LA over LV. These results suggest that the PDGF-JAK/STAT pathway may contribute to atrial-selective fibrosis in CHF and may be an interesting upstream therapeutic target.
- © 2013 by American Heart Association, Inc.