Hypoxia inducible factor-2alpha stabilization and maxi-K+ channel beta1-subunit gene repression by hypoxia in cardiac myocytes: role in preconditioning.
The Ca(2+)- and voltage-dependent K+ (maxi-K) channel beta(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 beta(1) protein may interact with mitochondrial proteins and that the beta(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-2alpha (Hif-2alpha) 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-2alpha. Interference of the beta(1)-subunit mRNA increases cardiomyocyte resistance to ischemia. Therefore, Hif-2alpha-mediated beta(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. Our work provides new perspectives for research on cardiac preconditioning.
Bautista
Lucía
L
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, 41013-Sevilla, Spain.
Castro
María J
MJ
López-Barneo
José
J
Castellano
Antonio
A
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D015687:Cell Hypoxia; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D019194:Ischemic Preconditioning; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000378:metabolism*; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D055550:Protein Stability; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1