title: Novel molecular mechanism of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-inducible factor-1alpha induced for impaired myocardial energy metabolism.
abstract: BACKGROUND
  Hypoxia-inducible factor (HIF)-1alpha is an important transcriptional factor that activates the gene expression of glycolytic enzymes, which are activated as compensation for impaired beta-oxidation of fatty acid in the failing heart. We reported that cardiac endothelin (ET)-1 expression is markedly increased in heart failure. The mechanism, however, is unknown. Because we found an HIF-1alpha binding site in the 5'-promoter region of the ET-1 gene, we hypothesized that HIF-1alpha is involved in this mechanism.
  
  
  RESULTS
  In rat cardiomyocytes, luciferase assay and electrophoretic mobility shift assay showed that HIF-1alpha transcriptionally activates ET-1 gene expression by direct interaction with the predicted DNA binding site in the 5'-promoter region. HIF-1alpha mRNA and ET-1 mRNA in the failing heart increased during the aggravation of heart failure in vivo in animal models, ie, rats with myocardial infarction and hamsters with cardiomyopathy. In cultured cardiomyocytes treated with a mitochondrial inhibitor, HIF-1alpha mRNA and ET-1 mRNA were markedly increased with activated glycolysis, and antisense oligonucleotide for HIF-1alpha largely inhibited the increased gene expression of ET-1.
  
  
  CONCLUSIONS
  The present study revealed a novel molecular mechanism of upregulation of myocardial ET-1 in heart failure, indicating that induction of HIF-1alpha to stimulate glycolysis as an adaptation in heart failure against impaired energy metabolism alternatively causes an elevation of cardiac ET-1 gene expression as a maladaptation.
authors.affiliation: Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kakinuma
authors.forename: T
authors.initials: T
authors.lastname: Miyauchi
authors.forename: K
authors.initials: K
authors.lastname: Yuki
authors.forename: N
authors.initials: N
authors.lastname: Murakoshi
authors.forename: K
authors.initials: K
authors.lastname: Goto
authors.forename: I
authors.initials: I
authors.lastname: Yamaguchi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D006224:Cricetinae; D016373:DNA, Antisense / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000502:physiology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors
chemical_list: D016373:DNA, Antisense; D004268:DNA-Binding Proteins; D019332:Endothelin-1; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D003035:Cobalt; D000255:Adenosine Triphosphate; D008156:Luciferases; C018021:cobaltous chloride