Abstract 16595: Chemical Inhibition of DRP-1 Suppresses ROS-Induced ROS-Release and Associated Arrhythmias in Intact Myocardium
Mitochondria are dynamic organelles that undergo fusion and fission events. These morphological changes affect myocyte susceptibility to apoptosis by promoting ROS generation. We hypothesized that altered mitochondrial network architecture also predisposes to ROS-mediated arrhythmias, which may be suppressed by chemical inhibition of mitochondrial fission.
Methods: Hearts were exposed to acute oxidative stress by H2O2perfusion with and without pre-treatment with MDIVI-1, a chemical inhibitor of fission. Optical superoxide (O2-) imaging or action potential (AP) mapping was used to measure spatio-temporal changes in metabolic and EP properties, respectively.
Results: Exposure of hearts (n=18) to short (10 min) episodes of H2O2 revealed a delayed O2- peak (P2) by high (≥200μ M, 8/8) but not lower (≤100μ M, 3/8) H2O2 concentrations (p<0.03). Consistent with RIRR, P2 was effectively suppressed by the IMAC blocker 4’-Cl-DZP (64μ M, n=4) and the synthetic O2- catalase mimetic, EUK-134 (50μ M, n=4). Examination of tissue sections using electron microscopy revealed highly fragmented circular mitochondria in H2O2 treated hearts (Fig). Remarkably, perfusion of hearts with MDIVI-1 (50μ M) abrogated RIRR by suppressing P2 (blue, p=0.03, n=3), protected against sustained arrhythmias and improved the structural integrity of the mitochondrial network (Fig). Specifically, H2O2 induced changes in mitochondrial form-factor (minor to major diameter ratio) was fully reversed by MDIVI-1. Finally, perfusion of hearts with MDIVI-1 alone did not alter baseline EP properties, as average APD (Ctrl: 73±6ms; MDIVI-1: 71±9ms, p=NS) and conduction velocity (Ctrl: 71±6cm/s; MDIVI-1: 67±8cm/s, p=NS) were unchanged.
Conclusions: Our findings: 1) establish the efficacy of suppressing pathological RIRR and associated arrhythmias through chemical inhibition of mitochondrial fission, and 2) demonstrate the potential EP safety of this approach.
- © 2012 by American Heart Association, Inc.