Unfavourable consequences of chronic cardiac HIF-1 stabilization

The hypoxia-inducible factor-1 (HIF-1) is the master modulator of hypoxic gene expression. The effects of chronically stabilized cardiac HIF-1 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-1 stabilization in the heart; (ii)to analyse long-term effects of HIF-1 stabilization with ageing and the ability of the HIF-1 overexpressing hearts to respond to increased mechanical load; and (iii)to analyse HIF-1 protein levels in failing heart samples. In a cardiac-specific HIF-1 transgenic mouse model, constitutive expression of HIF-1 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-1 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-1 in heart samples of patients with end-stage heart failure. Changes induced with transgenic cardiac HIF-1 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-1 protein levels in samples from human patients with cardiomyopathy, these data indicate that chronic HIF-1 stabilization drives autonomous pathways that add to disease progression.