title: Unfavourable consequences of chronic cardiac HIF-1α stabilization.
abstract: OBJECTIVE
  The hypoxia-inducible factor-1 (HIF-1) is the master modulator of hypoxic gene expression. The effects of chronically stabilized cardiac HIF-1α and its role in the diseased heart are not precisely known. The aims of this study were as follows: (i) to elucidate consequences of HIF-1α stabilization in the heart; (ii) to analyse long-term effects of HIF-1α stabilization with ageing and the ability of the HIF-1α overexpressing hearts to respond to increased mechanical load; and (iii) to analyse HIF-1α protein levels in failing heart samples.
  
  
  RESULTS
  In a cardiac-specific HIF-1α transgenic mouse model, constitutive expression of HIF-1α leads to changes in capillary area and shifts the cardiac metabolism towards glycolysis with a net increase in glucose uptake. Furthermore, Ca(2+) handling is altered, with increased Ca(2)(+) transients and faster intracellular [Ca(2+)] decline. These changes are associated with decreased expression of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a but elevated phosphorylation of phospholamban. HIF-1α transgenic mice subjected to transverse aortic constriction exhibited profound cardiac decompensation. Moreover, cardiomyopathy was also seen in ageing transgenic mice. In parallel, we found an increased stabilization of HIF-1α in heart samples of patients with end-stage heart failure.
  
  
  CONCLUSIONS
  Changes induced with transgenic cardiac HIF-1α possibly mediate beneficial effects in the short term; however, with increased mechanical load and ageing they become detrimental for cardiac function. Together with the finding of increased HIF-1α protein levels in samples from human patients with cardiomyopathy, these data indicate that chronic HIF-1α stabilization drives autonomous pathways that add to disease progression.
authors.affiliation: Department of Cardiovascular Physiology, Universitätsmedizin,  Georg-August-University Göttingen, Humboldtallee 23, 37073 Göttingen,  Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Hölscher
authors.forename: Katrin
authors.initials: K
authors.lastname: Schäfer
authors.forename: Sabine
authors.initials: S
authors.lastname: Krull
authors.forename: Katja
authors.initials: K
authors.lastname: Farhat
authors.forename: Amke
authors.initials: A
authors.lastname: Hesse
authors.forename: Monique
authors.initials: M
authors.lastname: Silter
authors.forename: Yun
authors.initials: Y
authors.lastname: Lin
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.forename: Patricia
authors.initials: P
authors.lastname: Thistlethwaite
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Dörthe M
authors.initials: DM
authors.lastname: Katschinski
authors.forename: Anke
authors.initials: A
authors.lastname: Zieseniss
mesh_terms: D000367:Age Factors; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; C506947:Atp2a2 protein, mouse