| First Author | Hölscher M | Year | 2012 |
| Journal | Cardiovasc Res | Volume | 94 |
| Issue | 1 | Pages | 77-86 |
| PubMed ID | 22258630 | Mgi Jnum | J:196629 |
| Mgi Id | MGI:5488878 | Doi | 10.1093/cvr/cvs014 |
| Citation | Holscher M, et al. (2012) Unfavourable consequences of chronic cardiac HIF-1alpha stabilization. Cardiovasc Res 94(1):77-86 |
| abstractText | AIMS: The hypoxia-inducible factor-1 (HIF-1) is the master modulator of hypoxic gene expression. The effects of chronically stabilized cardiac HIF-1alpha 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-1alpha stabilization in the heart; (ii) to analyse long-term effects of HIF-1alpha stabilization with ageing and the ability of the HIF-1alpha overexpressing hearts to respond to increased mechanical load; and (iii) to analyse HIF-1alpha protein levels in failing heart samples. METHODS AND RESULTS: In a cardiac-specific HIF-1alpha transgenic mouse model, constitutive expression of HIF-1alpha 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-1alpha 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-1alpha in heart samples of patients with end-stage heart failure. CONCLUSION: Changes induced with transgenic cardiac HIF-1alpha 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-1alpha protein levels in samples from human patients with cardiomyopathy, these data indicate that chronic HIF-1alpha stabilization drives autonomous pathways that add to disease progression. |
