title: Impaired Ca(2+)-handling in HIF-1alpha(+/-) mice as a consequence of pressure overload.
abstract: 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.
authors.affiliation: Department of Cardiovascular Physiology, Heart Center Georg-August University Göttingen, Humboldtallee 23, 37073 Göttingen, Germany.
authors.forename: Monique
authors.initials: M
authors.lastname: Silter
authors.forename: Harald
authors.initials: H
authors.lastname: Kögler
authors.forename: Anke
authors.initials: A
authors.lastname: Zieseniss
authors.forename: Jörg
authors.initials: J
authors.lastname: Wilting
authors.forename: Katrin
authors.initials: K
authors.lastname: Schäfer
authors.forename: Karl
authors.initials: K
authors.lastname: Toischer
authors.forename: Adam G
authors.initials: AG
authors.lastname: Rokita
authors.forename: Gerhard
authors.initials: G
authors.lastname: Breves
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Dörthe M
authors.initials: DM
authors.lastname: Katschinski
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D003331:Coronary Vessels / Q000033:anatomy & histology; D005260:Female; D006321:Heart / Q000502:physiology / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000473:pathology / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D040301:Vascular Endothelial Growth Factor Receptor-2; D002118:Calcium