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  • 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
    Griffith University Author(s)
    Wendt, Lauren
    Du Toit, Eugene
    Peart, Jason N.
    Headrick, John P.
    Year published
    2015
    Metadata
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    Abstract
    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 ...
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    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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    Conference Title
    The FASEB Journal
    Volume
    29
    Issue
    1_supplement
    DOI
    https://doi.org/10.1096/fasebj.29.1_supplement.1026.2
    Subject
    Biochemistry and cell biology
    Zoology
    Cardiology (incl. cardiovascular diseases)
    Pharmacology and pharmaceutical sciences
    Medical physiology
    Publication URI
    http://hdl.handle.net/10072/394649
    Collection
    • Conference outputs

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