Effects of Dynamin-Related Protein-1 (DRP-1) Inhibition with MDIVI-1 on Myocardial Injury, Mitochondrial Respiration and Stress-Signalling in the Murine Heart
Author(s)
Wendt, Lauren
See Hoe, Louise
Sachaphibulkij, Karishma
Du Toit, Eugene
Peart, Jason
Headrick, John
Year published
2015
Metadata
Show full item recordAbstract
Mitochondrial fission protein, dynamin-related protein-1 (DRP-1), may be a key determinant of cardiac resistance to ischemia-reperfusion (I-R) and other stresses. We examined the impact of I-R on myocardial expression of DRP-1 (together with Akt and Erk1/2), mitochondrial respiration, and injury in I-R hearts in 4mo male C57Bl/6 mice subject to DRP-1 inhibition. Functional recoveries of Langendorff perfused hearts subjected to 25 min ischemia/45 min reperfusion were significantly improved by pre-treatment with 1 µM MDIVI-1. Cell death (LDH efflux) was only modified by a higher 5 µM concentration. Protective effects were not ...
View more >Mitochondrial fission protein, dynamin-related protein-1 (DRP-1), may be a key determinant of cardiac resistance to ischemia-reperfusion (I-R) and other stresses. We examined the impact of I-R on myocardial expression of DRP-1 (together with Akt and Erk1/2), mitochondrial respiration, and injury in I-R hearts in 4mo male C57Bl/6 mice subject to DRP-1 inhibition. Functional recoveries of Langendorff perfused hearts subjected to 25 min ischemia/45 min reperfusion were significantly improved by pre-treatment with 1 µM MDIVI-1. Cell death (LDH efflux) was only modified by a higher 5 µM concentration. Protective effects were not replicated by an alternate inhibitor dynasore hydrate (1 µM). Ischemic insult repressed mitochondrial O2 consumption during early reperfusion, with a ~50% fall in complex I activity that was effectively reversed by MDIVI-1. Functional benefits were associated with MDIVI-1 dependent reductions in mitochondrial DRP-1 expression and cytosolic Erk1/2 phosphorylation during I-R, while phosphorylation of cardiac Akt was significantly augmented by MDIVI-1. A similar pattern was evident in parallel studies of H2O2 (400 µM) challenged H9c2 myoblasts, with MDIVI-1 negating oxidative-stress Erk1/2 phosphorylation whereas phosphoactivation of Akt was preserved. These data support a key role for DRP-1 in repressing I-R tolerance, mitochondrial function, and protective Akt phosphorylation (whilst also augmenting Erk1/2 activation). This role of DRP-1 in control of stress-resistance, mitochondrial function and survival-kinase signalling supports the potential value of targeting the protein to protect ischemic myocardium
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View more >Mitochondrial fission protein, dynamin-related protein-1 (DRP-1), may be a key determinant of cardiac resistance to ischemia-reperfusion (I-R) and other stresses. We examined the impact of I-R on myocardial expression of DRP-1 (together with Akt and Erk1/2), mitochondrial respiration, and injury in I-R hearts in 4mo male C57Bl/6 mice subject to DRP-1 inhibition. Functional recoveries of Langendorff perfused hearts subjected to 25 min ischemia/45 min reperfusion were significantly improved by pre-treatment with 1 µM MDIVI-1. Cell death (LDH efflux) was only modified by a higher 5 µM concentration. Protective effects were not replicated by an alternate inhibitor dynasore hydrate (1 µM). Ischemic insult repressed mitochondrial O2 consumption during early reperfusion, with a ~50% fall in complex I activity that was effectively reversed by MDIVI-1. Functional benefits were associated with MDIVI-1 dependent reductions in mitochondrial DRP-1 expression and cytosolic Erk1/2 phosphorylation during I-R, while phosphorylation of cardiac Akt was significantly augmented by MDIVI-1. A similar pattern was evident in parallel studies of H2O2 (400 µM) challenged H9c2 myoblasts, with MDIVI-1 negating oxidative-stress Erk1/2 phosphorylation whereas phosphoactivation of Akt was preserved. These data support a key role for DRP-1 in repressing I-R tolerance, mitochondrial function, and protective Akt phosphorylation (whilst also augmenting Erk1/2 activation). This role of DRP-1 in control of stress-resistance, mitochondrial function and survival-kinase signalling supports the potential value of targeting the protein to protect ischemic myocardium
View less >
Conference Title
The FASEB Journal
Volume
29
Issue
1_supplement
Subject
Biochemistry and cell biology
Zoology
Cardiology (incl. cardiovascular diseases)
Pharmacology and pharmaceutical sciences
Medical physiology