Open AccessHypoxia Inducible Factor-2α Stabilization and Maxi-K + Channel β 1 -Subunit Gene Repression by Hypoxia in Cardiac Myocytes
Author(s) -
Lucía Bautista,
María José Castro,
José LópezBarneo,
Antonio Castellano
Publication year - 2009
Publication title -
circulation research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.899
H-Index - 336
eISSN - 1524-4571
pISSN - 0009-7330
DOI - 10.1161/circresaha.108.190645
Subject(s) - hypoxia (environmental) , protein subunit , g alpha subunit , microbiology and biotechnology , cardioprotection , biology , myocyte , mitochondrion , inner mitochondrial membrane , psychological repression , depolarization , gene expression , ischemia , gene , chemistry , medicine , endocrinology , biochemistry , oxygen , organic chemistry
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-2α (Hif-2α) 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-2α. Interference of the β1 -subunit mRNA increases cardiomyocyte resistance to ischemia. Therefore, Hif-2α–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.