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Unfavourable consequences of chronic cardiac HIF-1α stabilization

Marion Hölscher, Katrin Schäfer, Sabine Krull, Katja Farhat, Amke Hesse, Monique Silter, Yun Lin, Bernd J. Pichler, Patricia Thistlethwaite, Ali El-Armouche, Lars. S. Maier, Dörthe M. Katschinski, Anke Zieseniss
DOI: http://dx.doi.org/10.1093/cvr/cvs014 77-86 First published online: 18 January 2012

Abstract

Aims 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.

Methods and 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, Ca2+ handling is altered, with increased Ca2+ transients and faster intracellular [Ca2+] 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.

Conclusion 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.

  • Hypoxia
  • Prolyl-4-hydroxylase domain enzymes
  • Hypoxia-inducible factor-1
  • Metabolism
  • Ischaemia
  • Cardiomyopathy
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