Redox regulation of the mitochondrial KATP channel in cardioprotection

The mitochondrial ATP-sensitive potassium channel (mK_ATP) is important in the protective mechanism of ischemic preconditioning (IPC). The channel is reportedly sensitive to reactive oxygen and nitrogen species, and the aim of this study was to compare such species in parallel, to build a more comprehensive picture of mK_ATP regulation. mK_ATP activity was measured by both osmotic swelling and Tl⁺ flux assays, in isolated rat heart mitochondria. An isolated adult rat cardiomyocyte model of ischemia-reperfusion (IR) injury was also used to determine the role of mK_ATP in cardioprotection by nitroxyl. Key findings were as follows: (i) mK_ATP was activated by O₂⁻ and H₂O₂ but not other peroxides. (ii) mK_ATP was inhibited by NADPH. (iii) mK_ATP was activated by S-nitrosothiols, nitroxyl, and nitrolinoleate. The latter two species also inhibited mitochondrial complex II. (iv) Nitroxyl protected cardiomyocytes against IR injury in an mK_ATP-dependent manner. Overall, these results suggest that the mK_ATP channel is activated by specific reactive oxygen and nitrogen species, and inhibited by NADPH. The redox modulation of mK_ATP may be an underlying mechanism for its regulation in the context of IPC. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.