Abstract 20308: Ca2+-mediated Proarrhythmic Activity via TRPC Channels Abolished by Gq Inhibitory Peptide
Introduction: Atrial fibrillation (AF) and congestive heart failure (HF) frequently coexist, preempting optimal treatment of either. While causes of AF and HF are multi-factorial, a common occurrence in both is increased Gq signaling. A consequence of increased Gq signaling is increased intracellular calcium (Ca2+), which is key in both Gq-mediated hypertrophy and in possible proarrhythmic activity such as Ca2+ waves. Canonical transient receptor potential channels (TRPCs) are Gq -activated Ca2+-permeable nonselective cation channels, and thus provide a means by which Gq signaling can bring about both hypertrophy/HF and proarrhythmic activity.
Methods: To evaluate whether TRPCs are involved in both hypertrophy and potential proarrhythmic activity, PCR and Western blotting were used to determine which TRPCs are present in normal and hypertrophic/failing canine atria (3 weeks ventricular tachypacing induced). Whereas confocal microscopy was used to ascertain the role of TRPCs in the modulation of intercellular Ca2+.
Results: A two-fold increase of Gq protein expression was found in hypertrophy/HF versus normal canine atria. PCR detected TRPC1, 3, 4, and 6 message in canine and human atria. TRPC3 protein expression was verified with western blotting. Phenylephrine (α1-adrenergic|Gq signaling)- induced Ca2+ waves and/or alternans in isolated canine atrial myocytes were eliminated by the TRPC antagonist, BTP2, and reduced with the TRPC3 specific antagonist, PYR3. A Gαq C-terminal peptide used to inhibit Gαq signaling resulted in the attenuation of Ca2+ waves and/or alternans in the setting of hypertrophy/HF (Figure).
Conclusions: Gq-mediated signaling contributes to proarrhythmic activity in the hypertrophied/failing heart through TRPC channels, notably TRPC3. Attenuation of this proarrhythmic activity utilizing a Gαq C-terminal peptide in the hypertrophy/HF may translate into a novel targeted therapy for AF, particularly in the setting of HF.
- © 2010 by American Heart Association, Inc.