Forkhead transcription factors coordinate expression of myocardial KATP channel subunits and energy metabolism.
Coordinate adaptation of myocyte metabolism and function is fundamental to survival of the stressed heart, but the mechanisms for this coordination remain unclear. Bioinformatics led us to discover that Foxs are key transcription factors involved. We performed experiments on the mouse atrial cell line HL-1, neonate rat heart myocytes, and an adult rat model of myocardial infarction. In electrophoretic mobility-shift assays, FoxO1 binds to the FoxO concensus site of the KATP channel subunit KIR6.1 promoter. In primary atrial culture, targeting FoxO1 and FoxO3 with siRNA specifically reduces mRNA expression of FoxO1 and -O3 and KIR6.1. Western blots, confocal immunofluorescence, and quantitative RT-PCR was applied for measuring expression of 10 Fox, 6 KATP channel subunits, and 12 metabolic genes. FoxF2, -O1, and -O3 strongly associate with expression of KATP channel subunits (in particular, KIR6.1, SUR1A and SUR2B) in different heart tissues and in the periinfarct zone of the left ventricle. Patch-clamp recordings demonstrate that molecular plasticity of these channels is matched by pharmacological plasticity and increased sensitivity to a metabolic challenge mimicked by the protonophore CCCP. A balance of FoxF2 and FoxO also regulates expression of at least 9 metabolic genes involved in setting the balance of glycolysis and beta-oxidation. Bioinformatics shows that the transcriptional mechanisms are highly conserved among chicken, mouse, rat, and human, and Fox are intimately linked to other metabolic sensors. Thus, FoxF2 and -O are key transcription factors coordinating expression of KATP channels and energy metabolism.
Philip-Couderc
Pierre
P
Department of Neuroscience, Hôpitaux Universitaires de Genève, Centre Médical Universitaire, Geneva, Switzerland.
Tavares
Nadia Isidoro
NI
Roatti
Angela
A
Lerch
René
R
Montessuit
Christophe
C
Baertschi
Alex J
AJ
D000818:Animals; D002478:Cells, Cultured; D019295:Computational Biology; D004734:Energy Metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D005786:Gene Expression Regulation; D054086:KATP Channels / Q000235:genetics*; D032342:Muscle Cells; D009203:Myocardial Infarction; D009419:Nerve Tissue Proteins; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D051381:Rats; D000071161:Forkhead Box Protein O1
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D054086:KATP Channels; D009419:Nerve Tissue Proteins; D024661:Potassium Channels, Inwardly Rectifying; C499515:FOXO3 protein, rat; C527561:FoxF2 protein, rat; C092520:uK-ATP-1 potassium channel; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1