Cardioprotective effect of fingolimod against calcium paradox-induced myocardial injury in the isolated rat heart

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dc.contributor.authorAlatrag, Fatma
dc.contributor.authorAmoni, Matthew
dc.contributor.authorKelly-Laubscher, Roisin
dc.contributor.authorGwanyanya, Asfree
dc.contributor.funderSouth African Medical Research Councilen
dc.contributor.funderNational Research Foundationen
dc.date.accessioned2022-02-15T10:33:03Z
dc.date.available2022-02-15T10:33:03Z
dc.date.issued2021-09-24
dc.date.updated2022-02-15T09:18:14Z
dc.description.abstractFingolimod (FTY720) inhibits Ca2+-permeable, Mg2+-sensitive channels called transient receptor potential melastatin 7 (TRPM7), but its effects on Ca2+ paradox (CP)-induced myocardial damage have not been evaluated. We studied the effect of FTY720 on CP-induced myocardial damage, and used other TRPM7 channel inhibitors nordihydroguaiaretic acid (NDGA) and Mg2+ to test if any effect of FTY720 was via TRPM7 inhibition. Langendorff-perfused Wistar rat hearts were treated with FTY720 or NDGA and subjected to a CP protocol consisting of Ca2+ depletion followed by Ca2+ repletion. Hearts of rats pre-treated with MgSO4 were also subjected to CP. Hemodynamic parameters were measured using an intraventricular balloon, and myocardial infarct size was quantified using triphenyltetrazolium chloride stain. TRPM7 proteins in ventricular tissue were detected using immunoblot analysis. FTY720, but not NDGA, decreased CP-induced infarct size. Both FTY720 and NDGA minimized the CP-induced elevation of left ventricular end-diastolic pressure, but only FTY720 ultimately improved ventricular developed pressure. Mg2+ pre-treatment had effect neither on CP-induced infarct size, hemodynamic parameters during CP, nor the level TRPM7 protein expression in ventricular tissue. Overall, FTY720 attenuated CP-induced myocardial damage, with potential therapeutic implications on Ca2+-mediated cardiotoxicity. However, the cardioprotective mechanism of FTY720 seems to be unrelated to TRPM7 channel modulation.en
dc.description.sponsorshipSouth African Medical Research Council (MRC SIR Grant number 29841); National Research Foundation (NRF Grant numbers 85768 and 91514)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationAlatrag, F., Amoni, M., Kelly-Laubscher, R. and Gwanyanya, A. (2021) 'Cardioprotective effect of fingolimod against calcium paradox-induced myocardial injury in the isolated rat heart', Canadian Journal of Physiology and Pharmacology, 100(2), pp. 134-141. doi: 10.1139/cjpp-2021-0381en
dc.identifier.doi10.1139/cjpp-2021-0381en
dc.identifier.eissn1205-7541
dc.identifier.endpage141en
dc.identifier.issn0008-4212
dc.identifier.issued2en
dc.identifier.journaltitleCanadian Journal of Physiology and Pharmacologyen
dc.identifier.startpage134en
dc.identifier.urihttps://hdl.handle.net/10468/12566
dc.identifier.volume100en
dc.language.isoenen
dc.publisherCanadian Science Publishingen
dc.rights© 2021, the Authors. Published by Canadian Science Publishing.en
dc.subjectCardiacen
dc.subjectCalcium paradoxen
dc.subjectFingolimoden
dc.subjectIon channelsen
dc.subjectTRPM7en
dc.titleCardioprotective effect of fingolimod against calcium paradox-induced myocardial injury in the isolated rat hearten
dc.typeArticle (peer-reviewed)en
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