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(Circulation Research. 2009;104:1364.)
© 2009 American Heart Association, Inc.

Cellular Biology

Hypoxia Inducible Factor-2 Stabilization and Maxi-K⁺ Channel β₁-Subunit Gene Repression by Hypoxia in Cardiac Myocytes

Role in Preconditioning

Lucía Bautista, María J. Castro, José López-Barneo, Antonio Castellano

From the Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Cientificas/Universidad de Sevilla, Spain.

Correspondence to Dr Antonio Castellano, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, 41013-Sevilla, Spain. E-mail acastell{at}us.es

The Ca²⁺- and voltage-dependent K⁺ (maxi-K) channel β₁-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 β₁ protein may interact with mitochondrial proteins and that the β₁-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 β₁-subunit mRNA increases cardiomyocyte resistance to ischemia. Therefore, Hif-2–mediated β₁-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. Our work provides new perspectives for research on cardiac preconditioning.

Key Words: hypoxia inducible factor-2 • hypoxic preconditioning • maxi-K channel β₁-subunit • cardiomyocyte • small interfering RNA