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dc.contributor.authorWendt, Lauren
dc.contributor.authorVider, Jelena
dc.contributor.authorSee Hoe, Louise E
dc.contributor.authorDu Toit, Eugene F
dc.contributor.authorPeart, Jason N
dc.contributor.authorHeadrick, John P
dc.description.abstractDynamin-related protein-1 (DRP-1) dependent mitochondrial fission may influence cardiac tolerance to ischemic or oxidative stress, presenting a potential 'cardioprotective' target. Effects of dynamin inhibitors MDIVI-1 and dynasore on injury, mitochondrial function and signaling proteins were assessed in distinct models: ischemia-reperfusion (I-R) in mouse hearts, and oxidative stress in rat H9c2 cardiomyoblasts. Hearts exhibited substantial cell death (~40 IU LDH efflux) and dysfunction (~40 mmHg diastolic pressure, ~40% contractile recovery) following 25 min ischemia. Pre-treatment with 1 µM MDIVI-1 reduced dysfunction (30 mmHg diastolic pressure, ~55% recovery) and delayed without reducing overall cell death, whereas 5 µM MDIVI-1 reduced overall death while paradoxically exaggerating dysfunction. Post-ischemic expression of mitochondrial DRP-1 and phospho-activation of ERK1/2 were reduced by MDIVI-1. Conversely, 1 µM dynasore worsened cell death and reduced non-mitochondrial DRP-1. Post-ischemic respiratory fluxes were unaltered by MDIVI-1, although a 50% fall in complex-I flux control ratio was reversed. In H9c2 myoblasts stressed with 400 µM H2O2, treatment with 50 µM MDIVI-1 preserved metabolic (MTT assay) and mitochondrial (basal respiration) function without influencing survival. This was associated with differential signaling responses, including reduced early vs. increased late phospho-activation of ERK1/2, increased phospho-activation of AKT, and differential changes in determinants of autophagy (reduced LC3B-II/I vs. increased Parkin) and apoptosis (reduced PARP cleavage vs. increased BAX:BCL2). These data show MDIVI-1 (not dynasore) confers some benefit during I-R/oxidative stress. However, despite mitochondrial and metabolic preservation, MDIVI-1 exerts mixed effects on cell death vs. dysfunction, potentially reflecting differential changes in survival kinase, autophagy and apoptosis pathways.
dc.publisherAmerican Society for Pharmacology & Experimental Therapeutics (ASPET)
dc.relation.ispartofjournalJournal of Pharmacology and Experimental Therapeutics
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.titleComplex Effects of Putative DRP-1 Inhibitors on Stress Responses in Mouse Heart and Rat Cardiomyoblasts
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationWendt, L; Vider, J; See Hoe, LE; Du Toit, EF; Peart, JN; Headrick, JP, Complex Effects of Putative DRP-1 Inhibitors on Stress Responses in Mouse Heart and Rat Cardiomyoblasts, Journal of Pharmacology and Experimental Therapeutics, pp. jpet.119.258897-jpet.119.258897
gro.description.notepublicThis publication has been entered into Griffith Research Online as an Advanced Online Version
gro.hasfulltextNo Full Text
gro.griffith.authorWendt, Lauren
gro.griffith.authorPeart, Jason N.
gro.griffith.authorDu Toit, Eugene
gro.griffith.authorHeadrick, John P.
gro.griffith.authorVider, Jelena
gro.griffith.authorSee Hoe, Louise

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