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Article Dans Une Revue European Journal of Pharmacology Année : 2019

The CO-releasing molecule CORM-3 protects adult cardiomyocytes against hypoxia-reoxygenation by modulating pH restoration

Lolita Portal
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Didier Morin
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Roberto Motterlini
Sandrine Pons

Résumé

Several studies have reported that CORM-3, a water-soluble carbon monoxide releasing molecule, elicits cardioprotection against myocardial infarction but the mechanism remains to be investigated. Numerous reports indicate that inhibition of pH regulators, the Na + /H + exchanger (NHE) and Na + /HCO3symporter (NBC), protect cardiomyocytes from hypoxia/reoxygenation injury by delaying the intracellular pH (pHi) recovery at reperfusion. Our goal was to explore whether CORM-3-mediated cytoprotection involves the modulation of pH regulation. When added at reoxygenation, CORM-3 (50 µM) reduced the mortality of cardiomyocytes exposed to 3h of hypoxia and 2h of reoxygenation in HCO3-buffered solution. This effect was lost when using inactive iCORM-3, which is depleted of CO and used as control, thus implicating CO as the mediator of this cardioprotection. Interestingly, the cardioprotective effect of CORM-3 was abolished by switching to a bicarbonate-free medium. This effect of CORM-3 was also inhibited by 5-hydroxydecanoate, a mitochondrial ATP-dependent K + (mKATP) channel inhibitor (500 µM) or PD098059, a MEK1/2 inhibitor (10 µM). In additional experiments and in the absence of hypoxia-reoxygenation, intracellular pH was monitored in cardiomyocytes exposed to cariporide to block NHE activity. CORM-3 inhibited alkalinisation and this effect was blocked by PD098059 and 5-HD. In conclusion, CORM-3 protects the cardiomyocyte against hypoxia-reoxygenation injury by inhibiting a bicarbonate transporter at reoxygenation, probably the Na + /HCO3symporter. This cardioprotective effect of CORM-3 requires the activation of mKATP channels and the activation of MEK1/2.
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Dates et versions

hal-02392506 , version 1 (24-11-2020)

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Lolita Portal, Didier Morin, Roberto Motterlini, Bijan Ghaleh, Sandrine Pons. The CO-releasing molecule CORM-3 protects adult cardiomyocytes against hypoxia-reoxygenation by modulating pH restoration. European Journal of Pharmacology, 2019, 862, pp.172636. ⟨10.1016/j.ejphar.2019.172636⟩. ⟨hal-02392506⟩
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