Abstract 18394: Heat Shock Protein Inducer Geranylgeranylacetone (gga) Protects Against Atrial Fibrillation via the PI3K Pathway
There is evidence suggesting that heat shock proteins protect against clinical atrial fibrillation (AF) by mediating cellular stress. Recently, investigators reported that the HSP-inducing compound GGA prevents the induction of atrial remodeling by AF and attenuates the promotion of AF. An important factor in AF promotion is that atrial cardiomyocytes have constitutively active acetylcholine-activated K+ (IKACh) current, which is enhanced by tachycardia. However, it is whether GGA regulates IKACh remains unclear. We examined the effect of GGA on IKACh current in mouse atrial cardiomyocytes and in an in vitro atrial cell line (HL-1) model of tachycardia remodeling.
Methods: In the present study, the IKACh current was recorded using a nystatin-perforated whole cell patch-clamp technique following activation by acetylcholine (10 μM for 2 min). After the measurement of baseline IKACh current, cardiomyocytes were treated with GGA 10 μM for 10 min and IKACh current was re-measured. HL-1 cells were tachypaced via stimulation at 5 Hz with square-wave 10-ms pulses. The results of paced cells were compared with non-paced cells studied in parallel.
Results: IKACh current in atrial cardiomyocytes treated with acetylcholine was significantly increased, but this was markedly attenuated by GGA 10 μM treatment (n=5, peak: 54±11.2%, quasi-steady-state: 58±11.4%, p<0.001). In addition, GGA recovered acetylcholine-induced APD shortening. GGA-treated paced myocytes exhibited significant increases in all major HSPs, including HSP90, HSP70 and HSP27. Also, GGA attenuated tachypacing-induced reactive oxygen species (ROS) and nitric oxide (NO) production. To evaluate the pathway of GGA in the regulation of IKACh, co-treatment with GGA and wortmannin, a PI3K inhibitor, was performed, and the results indicated that WMN completely blocked GGA’s IKACh current-blocking effect.
Conclusion: This study provides important evidence that HSP inducer GGA achieves potent antiarrhythmic effects by inhibiting IKACh and blocking ROS production, which underlies electrical remodeling in mammalian atrial cardiomyocytes. Furthermore, the results of this study indicate the possible therapeutic benefits of GGA, which can enhance the expression of HSPs in patients with AF.
Author Disclosures: T. Cha: None. E. Choi: None. G. Yu: None. B. Kim: None. D. Park: None.
- © 2016 by American Heart Association, Inc.