Hypoxia Inducible Factor-2α Stabilization and Maxi-K ⁺ Channel β ₁ -Subunit Gene Repression by Hypoxia in Cardiac Myocytes

Abstract

Abstract-The Ca 2ϩ -and voltage-dependent K ϩ (maxi-K) channel ␤ 1 -subunit mRNA is particularly abundant in cardiomyocytes but its functional role is unknown. This is intriguing because functional maxi-K channels are not found in cardiomyocyte plasmalemma, although they have been suggested to be in the inner mitochondrial membrane and participate in cardioprotection. We report here that ␤ 1 protein may interact with mitochondrial proteins and that the ␤ 1 -subunit gene (KCNMB1) is repressed by sustained hypoxia in dispersed cardiomyocytes as well as in heart intact tissue. The effect of hypoxia is time-and dose-dependent, is mimicked by addition of reactive oxygen species, and selectively requires hypoxia inducible factor-2␣ (Hif-2␣) stabilization. We have observed that adaptation to hypoxia exerts a protective role on cardiomyocytes subjected to ischemia and that, unexpectedly, this form of preconditioning absolutely depends on Hif-2␣. Interference of the ␤ 1 -subunit mRNA increases cardiomyocyte resistance to ischemia. Therefore, Hif-2␣-mediated ␤ 1 -subunit gene repression is a previously unknown mechanism that could participate in the gene expression program triggered by sustained hypoxia to prevent deleterious mitochondrial depolarization and ATP deficiency in cardiac cells. Key Words: hypoxia inducible factor-2␣ Ⅲ hypoxic preconditioning Ⅲ maxi-K channel ␤ 1 -subunit Ⅲ cardiomyocyte Ⅲ small interfering RNA

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