Abstract 20280: Suppression of Post-Ischemic Arrhythmias by a Selective Small Molecule Inhibitor of Dynamin and Dynamin Related Protein 1
Introduction: Dynamins (Dnm) and Dnm related protein 1 (DRP1) play central roles in cell biology by regulating pathways involved in endocytosis and mitochondrial fission, respectively. Disruption of both processes has been implicated in cardiac dysfunction associated with ischemia reperfusion (IR) injury. Recently, the small noncompetitive Dnm GTPase inhibitor, Dynasore (Dyn) was shown to improve cardiac lusitropy in response to IR injury. Here, we investigated the electrophysiological (EP) consequences of Dyn under conditions of acute oxidative stress (OS) caused by H2O2 challenge or IR injury.
Methods: Rat hearts (N=39) were treated with a low (1uM) or high (5uM) concentration of Dyn for 35 or 120 min before challenge with H2O2 (200uM) or no flow ischemia for 12 min followed by reperfusion. High resolution optical mapping was used to measure spatio-temporal changes in the action potential and mitochondrial membrane potential (MMP) across the heart.
Results: Pretreatment of hearts with 1um Dyn for 120 min but not 35 min suppressed the incidence of reperfusion arrhythmias compared to untreated hearts (5/12 vs 6/7). Investigation of the EP substrate revealed marked attenuation of conduction slowing with no change in APD in response to ischemia in Dyn treated hearts. These beneficial effects were abrogated by selective PKC inhibition in an additional subset of experiments (n=3). Similar to IR injury, challenge of hearts with H2O2 for 30 min was associated with a significantly (p=0.0019) lower arrhythmia score in Dyn-treated compared to untreated hearts. Underlying this reduction in arrhythmic vulnerability was the prevention of H2O2 induced MMP depolarization and attenuation of MMP heterogeneity. Importantly, treatment of hearts with a higher (5uM) concentration of Dyn that is more consistent with inhibition of clatherin mediated endocytosis resulted in the rapid elevation of coronary perfusion pressure, MMP depolarization, and early onset of arrhythmias.
Conclusions: At low but not high concentrations, Dyn exerts potent anti-arrhythmic activity likely by preventing OS-induced mitochondrial fission and associated dysfunction. Selective DRP1 inhibition may be a novel strategy for arrhythmia suppression in ischemic heart disease.
Author Disclosures: J. Hu: None. A. Chavez: None. C. Xie: None. F.G. Akar: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.