The CO-releasing molecule CORM-3 protects adult cardiomyocytes against hypoxia-reoxygenation by modulating pH restoration.
Eur J Pharmacol
; 862: 172636, 2019 Nov 05.
Article
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| MEDLINE
| ID: mdl-31491405
ABSTRACT
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+/HCO3- symporter (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⯵M) reduced the mortality of cardiomyocytes exposed to 3â¯h of hypoxia and 2â¯h 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⯵M) or PD098059, a MEK1/2 inhibitor (10⯵M). 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+/HCO3- symporter. This cardioprotective effect of CORM-3 requires the activation of mKATP channels and the activation of MEK1/2.
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Bases de datos:
MEDLINE
Asunto principal:
Compuestos Organometálicos
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Daño por Reperfusión Miocárdica
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Sustancias Protectoras
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Miocitos Cardíacos
Idioma:
En
Revista:
Eur J Pharmacol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Francia