Abstract 14853: The Potential Role of Fibroblast Kv Channels in Atrial Fibrotic Profibrillatory Remodeling
Background: Cardiac fibroblasts (FBs) maintain normal cardiac structure but also govern structural remodeling. CHF, a common cause of AF, causes major structural changes that contribute to the AF substrate. Little is known about the molecular basis and functional importance of FB voltage dependent (Kv) channels, which were the object of this study.
Methods: Atrial FBs were isolated from control (CTL) and CHF dogs (2 week ventricular tachypacing 240 bpm). Kv currents were recorded with whole-cell patch clamp. Mitotic activity was examined with flow cytometry. mRNA was quantified by qPCR.
Results: Kv currents displayed fast activation (τ= ~ 1.7 ms) with slow and partial inactivation compatible with C-type processes. Kv channel reversal potential followed a Nernst relationship with [K+]o (Fig. A), indicating K+ selectivity, and inactivation V1/2 was about -35 mV, shifting 10 mV at 100 mM [K+]o, for both CTL and CHF (Fig. B), indicating similar biophysics. Currents were sensitive to a nonselective Kv channel blocker, 4-AP (IC50= 49 μM) and to a highly-selective Kv1.5 channel blocker, DPO-1 (IC50=271 nM, Fig. C), with over 85% of current inhibited by 1 μM DPO-1. Kv current was not significantly affected by 20 nM angiotoxin-1 (Kv1.3 blocker) or 100 nM dendrotoxin (Kv1.1, 1.2, and 1.6 blocker). CHF strongly downregulated 1 μM DPO-1 sensitive currents (Fig. D). DPO-1 (300 nM) treatment of cultured FBs for 24 hours significantly increased dividing G2/M cell percentage (Fig. E), indicating that Kv suppression enhances FB proliferation. CHF downregulated Kv1.5 expression by 61% (Fig. F). Kv1.3, 1.6, 2.1, and 3.1 expression levels were low and unaltered by CHF.
Conclusions: Kv1.5 is the principal FB Kv channel α subunit, and channel expression is strongly downregulated in CHF. Kv1.5 channel downregulation promotes FB proliferation, suggesting that it may have an important functional role in CHF-induced AF-promoting fibrosis and may be of interest as a novel upstream anti-AF target.
- © 2013 by American Heart Association, Inc.