Mechanism of Na⁺/Ca²⁺ Exchanger Activation by Hydrogen Peroxide in Guinea-Pig Ventricular Myocytes

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Using the whole-cell voltage clamp, we examined the mechanism of activation of the Na⁺/Ca²⁺ exchanger (NCX) by hydrogen peroxide (H₂O₂) in isolated guinea-pig cardiac ventricular myocytes. Exposure to H₂O₂ increased the NCX current. The effect was inhibited by cariporide, an inhibitor of the Na⁺/H⁺ exchanger (NHE), suggesting that there are NHE-dependent and -independent pathways in the effect of H₂O₂ on NCX. In addition, both pathways were blocked by edaravone, a hydroxyl radical (•OH) scavenger; pertussis toxin, a Gα_i/o protein inhibitor; and U0126, an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK). On the other hand, wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, inhibited only the NHE-dependent pathway, while PP2, a Src family protein tyrosine kinase inhibitor, inhibited only the NHE-independent pathway. Taken together, our data suggest that H₂O₂ increases the NCX current via two signal transduction pathways. The common pathway is the conversion of H₂O₂ to •OH, which activates Gα_i/o protein and a mitogen-activated protein (MAP) kinase signaling pathway. Then, one pathway activates NHE with a PI3K-dependent mechanism and indirectly increases the NCX current. Another pathway involves activation of a Src family tyrosine kinase.