Pflugers Archiv : European journal of physiology

Impaired Ca(2+)-handling in HIF-1alpha(+/-) mice as a consequence of pressure overload.

PMID 19898976


The hypoxia-inducible factor (HIF)-1 is critically involved in the cellular adaptation to a decrease in oxygen availability. The influence of HIF-1alpha for the development of cardiac hypertrophy and cardiac function that occurs in response to sustained pressure overload has been mainly attributed to a challenged cardiac angiogenesis and cardiac hypertrophy up to now. Hif-1alpha (+/+) and Hif-1alpha (+/-) mice were studied regarding left ventricular hypertrophy and cardiac function after being subjected to transverse aortic constriction (TAC). After TAC, both Hif-1alpha (+/+) and Hif-1alpha (+/-) mice developed left ventricular hypertrophy with increased posterior wall thickness, septum thickness and increased left ventricular weight to a similar extent. No significant difference in cardiac vessel density was observed between Hif-1alpha (+/+) and Hif-1alpha (+/-) mice. However, only the Hif-1alpha (+/-) mice developed severe heart failure as revealed by a significantly reduced fractional shortening mostly due to increased end-systolic left ventricular diameter. On the single cell level this correlated with reduced myocyte shortenings, decreased intracellular Ca(2+)-transients and SR-Ca(2+) content in myocytes of Hif-1a (+/-) mice. Thus, HIF-1alpha can be critically involved in the preservation of cardiac function after chronic pressure overload without affecting cardiac hypertrophy. This effect is mediated via HIF-dependent modulation of cardiac calcium handling and contractility.