Novel molecular mechanism of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-induciblefactor-1 alpha induced for impaired myocardial energy metabolism

Background-Hypoxia-inducible factor (HIF)-1 alpha is an important transcrip tional factor that activates the gene expression of glycolytic enzymes, whi ch are activated as compensation for impaired beta -oxidation of fatty acid in the failing heart. We reported that cardiac endothelin (ET)-1 expressio n is markedly increased in heart failure. The mechanism, however, is unknow n. Because we found an HIF-1 alpha binding site in the 5 ' -promoter region of the ET-1 gene, we hypothesized that HIF-1 alpha is involved in this mec hanism. Methods and Results-In rat cardiomyocytes, luciferase assay and electrophor etic mobility shift assay showed that HIF-1 alpha transcriptionally activat es ET-1 gene expression by direct interaction with the predicted DNA bindin g site in the 5 ' -promoter region. HIF-1 alpha mRNA and ET-1 mRNA in the f ailing heart increased during the aggravation of heart failure in vivo in a nimal models, ie, rats with myocardial infarction and hamsters with cardiom yopathy. In cultured cardiomyocytes treated with a mitochondrial inhibitor, HIF-1 alpha mRNA and ET-1 mRNA were markedly increased with activated glyc olysis, and antisense oligonucleotide for HIF-1 alpha largely inhibited the increased gene expression of ET-1. Conclusions-The present study revealed a novel molecular mechanism of upreg ulation of myocardial ET-1 in heart failure, indicating that induction of H IF-1 alpha to stimulate glycolysis as an adaptation in heart failure agains t impaired energy metabolism alternatively causes an elevation of cardiac E T-1 gene expression as a maladaptation.