U955-IMRB, Equipe 03, Inserm, UPEC, Ecole Nationale Vétérinaire d'Alfort, Créteil, France.
U955-IMRB, Equipe 12, Inserm, UPEC, Créteil, France.
Eur J Pharmacol. 2019 Nov 5;862:172636. doi: 10.1016/j.ejphar.2019.172636. Epub 2019 Sep 3.
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/HCO 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 μM) reduced the mortality of cardiomyocytes exposed to 3 h of hypoxia and 2 h of reoxygenation in HCO-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 (mK) 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/HCO symporter. This cardioprotective effect of CORM-3 requires the activation of mK channels and the activation of MEK1/2.
已有多项研究报道，水溶性一氧化碳释放分子 CORM-3 可发挥心肌保护作用，减轻心肌梗死，但具体机制仍待研究。大量报道表明，抑制 pH 调节剂、钠氢交换体（NHE）和钠碳酸氢盐协同转运体（NBC）可通过延迟再灌注时的细胞内 pH（pHi）恢复，减轻心肌细胞缺氧/复氧损伤。我们的目标是探讨 CORM-3 介导的细胞保护作用是否涉及 pH 调节的调节。在复氧时加入 CORM-3（50μM），可降低在 HCO3-缓冲液中暴露于 3 小时缺氧和 2 小时复氧的心肌细胞的死亡率。当使用无 CO 且作为对照的失活 iCORM-3 时，该作用消失，提示 CO 是这种心脏保护作用的介导物。有趣的是，CORM-3 的心脏保护作用在切换至不含碳酸氢盐的培养基中时被消除。CORM-3 的这种作用也被线粒体 ATP 依赖性 K（mK）通道抑制剂 5-羟基癸酸（500μM）或 MEK1/2 抑制剂 PD098059（10μM）抑制。在其他实验中，在没有缺氧/复氧的情况下，监测暴露于 cariporide 以阻断 NHE 活性的心肌细胞内的 pH。CORM-3 抑制碱化，该作用被 PD098059 和 5-HD 阻断。总之，CORM-3 通过在复氧时抑制碳酸氢盐转运体来保护心肌细胞免受缺氧/复氧损伤，可能是 Na/HCO 协同转运体。CORM-3 的这种心脏保护作用需要 mK 通道的激活和 MEK1/2 的激活。
