Cardioprotective effect of fingolimod against calcium paradox-induced myocardial injury in the isolated rat heart
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Accepted Version
Date
2021-09-24
Authors
Alatrag, Fatma
Amoni, Matthew
Kelly-Laubscher, Roisin
Gwanyanya, Asfree
Journal Title
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Publisher
Canadian Science Publishing
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Abstract
Fingolimod (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.
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Keywords
Cardiac , Calcium paradox , Fingolimod , Ion channels , TRPM7
Citation
Alatrag, 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-2021-0381
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© 2021, the Authors. Published by Canadian Science Publishing.