Abstract 15424: Prolonged Inhibition of Mitochondrial Fission Enhances Myocardial Injury in Response to Ischemia/Reperfusion
Mitochondrial quality is maintained through mitochondrial dynamics (fusion and fission) and mitophagy. Although dynamin-related protein 1 (Drp1) is crucial in mediating mitochondrial fission, which is essential for elimination of damaged mitochondria by mitophagy, initial suppression of Drp1 by mdivi-1 is reported to protect against cardiac ischemia/reperfusion (I/R) injury. This study aims to clarify the effect of prolonged inhibition of fission on I/R injury.
One-time treatment of C57BL6 mice with mdivi-1 just before I/R significantly reduced the myocardial infarct/area at risk (MI/AAR) compared to vehicle treatment (37.4±5.2 vs. 24.3±8.4%, p<0.05). Repeated applications of mdivi-1 (1.2 mg/kg/day for 7 days) did not significantly reduce left ventricular systolic function, but significantly increased mitochondrial mass, assessed by electron microscopy (relative mitochondrial mass: 1.0±0.3 vs. 1.6±0.4%, p<0.05), reduced mitochondrial function, as determined by mitochondrial swelling assays (decrease in OD540nm: 1.9±0.6 vs. 5.2±1.1%, p<0.05) and ATP production (relative ATP production: 1.02±0.18 vs. 0.68±0.29%, p<0.05), and significantly enhanced the MI/AAR after I/R compared to vehicle treatment (39.2±4.8 vs. 48.4±5.6%, p<0.05).
To examine the effect of mdivi-1 treatment on cardiac apoptosis in vitro, cardiomyocytes (CMs) were treated with chelerythrine (10 μM), an inducer of apoptosis, with or without mdivi-1. Mdivi-1 treatment at 50 μM for 1 hour increased CM survival in response to chelerythrine compared to vehicle treatment (68.7±15.4 vs. 98.3±17.2%, p<0.05). Treatment with 50 μM mdivi-1 every 24 hours for 1 week induced fused mitochondria at baseline, inhibited mitochondrial fission, significantly suppressed glucose deprivation-induced autophagic flux, as evaluated with mRFP-GFP-LC3, and decreased CM viability time-dependently compared to vehicle treatment (48Hr: 96.3±6.2 vs. 81.6±12.5%, p<0.05, 72Hr: 94.8±5.7 vs. 68.3±15.2%, p<0.05, 98Hr: 92.3±7.2 vs. 51.8±16.3%, p<0.05).
Thus, while initial inhibition of fission by one-time treatment with mdivi-1 appears to be protective, prolonged inhibition by long-term treatment enhances I/R injury, possibly due to prolonged inhibition of autophagy.
Author Disclosures: Y. Ikeda: None. P. Zhai: None. M. Ohishi: None. J. Sadoshima: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.