The Hypoxia inducible factor-1 (HIF-1) is the master modulator of hypoxic gene expression. HIF-mediated changes in the heart, the effects of chronically stabilized cardiac HIF-1a and its association to the diseased heart are not precisely known.

The objectives of this study were (I) to analyze HIF-1a protein levels in failing heart samples, (II) to elucidate consequences of HIF-1a stabilization in the heart and (III) to analyze long term effects of HIF-1a stabilization with aging as well as the flexibility of the HIF-1a overexpressing hearts to respond to increased mechanical load in a cardiac specific HIF-1a transgenic (tg) mouse model.

HIF-1a is stabilized in heart samples of patients with end stage heart failure. In the HIF-1a tg mouse model the constitutive expression of HIF-1a leads to changes in capillary area and shifts the cardiac metabolism toward anaerobic glycolysis with a net increase of glucose uptake. Furthermore Ca²⁺ handling is altered with significantly increased Ca²⁺-transients and faster [Ca²⁺]i decline. These changes are associated with depressed expression of the SR Ca²⁺-ATPase and elevated phospholamban phosphorylation. After subjected to transverse aortic constriction the HIF-1a tg mice exhibited profound cardiac decompensation. Moreover, cardiomyopathy was also seen in aging mice.

Transgenic cardiac HIF-1a induced changes possibly mediate short term beneficial effects but are, with increased mechanical load and aging, detrimental for cardiac function. Together with the finding of increased HIF-1a protein levels in cardiomyopathy heart samples these data indicate that chronic HIF-1a stabilization drives autonomous pathways, which add to disease progression.