Activation of negative regulators of the hypoxia-inducible factor (HIF) pathway in human end-stage heart failure.
The hypoxia-inducible transcription factor HIF is induced early in acute myocardial ischemia in humans, but it is unknown whether this activation of HIF persists during chronic heart failure. The HIF system was characterized in left ventricular myocardia from 18 explanted failing hearts and 11 non-failing donor hearts by quantitative RT-PCR and Western analysis. HIF-1alpha mRNA levels were significantly decreased while its natural antisense transcript aHIF was nearly twofold higher (p<0.01) in failing myocardia than in control hearts. Moreover, compared to donor hearts a significantly increased expression of HIF-3alpha, which may act as a competitive inhibitor of HIF-1/2alpha activity, and PHD3, which upon hydroxylation of prolyl residues directs HIF-alpha subunits towards proteasomal degradation, was observed in the failing myocardium. Although negative regulators of HIF were induced, the HIF pathway obviously remains activated in chronic human heart failure, because prototype HIF target genes, such as ABCG2, VEGF, and BNIP3, were significantly induced.
Zolk
Oliver
O
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Fahrstr. 17, 91054 Erlangen, Germany. Zolk@pharmakologie.med.uni-erlangen.de
Solbach
Thomas F
TF
Eschenhagen
Thomas
T
Weidemann
Alexander
A
Fromm
Martin F
MF
D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000235:genetics / Q000378:metabolism; D002908:Chronic Disease; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016372:RNA, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000099162:Endothelial PAS Domain-Containing Protein 1
D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046988:Proteasome Endopeptidase Complex; D016372:RNA, Antisense; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C116973:HIF3A protein, human