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Type of publication: Journal Article
Type of document: Full Paper

Year: 2004

Authors: Huang, Y; Hickey, RP; Yeh, JL; Liu, D; Dadak, A; Young, LH; Johnson, RS; Giordano, FJ

Title: Cardiac myocyte-specific HIF-1alpha deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart.

Source: Faseb J (18), 10 1138-1140.

Authors Vetmeduni Vienna:

Dadak Agnes

Project(s): Activation and function of hypoxia inducible transcription factors

At a resting pulse rate the heart consumes almost twice-as much oxygen per gram tissue as the brain and more than 43 times more than resting skeletal muscle (1). Unlike skeletal muscle, cardiac muscle cannot sustain anaerobic metabolism. Balancing oxygen demand with availability is crucial to cardiac function and survival, and regulated gene expression is a critical element of maintaining this balance. We investigated the role of the hypoxia-inducible transcription factor HIF-1alpha in maintaining this balance under normoxic conditions. Cardiac myocyte-specific HIF-1alpha gene deletion in the hearts of genetically engineered mice caused reductions in contractility, vascularization, high-energy phosphate content, and lactate production. This was accompanied by altered calcium flux and altered expression of genes involved in calcium handling, angiogenesis, and glucose metabolism. These findings support a central role for HIF-1alpha in coordinating energy availability and utilization in the heart and have implications for disease states in which cardiac oxygen delivery is impaired. Heart muscle requires a constant supply of oxygen. When oxygen supply does not match myocardial demand cardiac contractile dysfunction occurs, and prolongation of this mismatch leads to apoptosis and necrosis. Coordination of oxygen supply and myocardial demand involves immediate adaptations, such as coronary vasodilatation, and longer-term adaptations that include altered patterns of gene expression (2-4). How the expression of multiple genes is coordinated with oxygen availability in the heart and the impact of oxygen-dependent gene expression on cardiac function are insufficiently understood. Further elucidating these relationships may help clarify the molecular pathology of various cardiovascular disease states, including ischemic cardiomyopathy and myocardial hibernation (5, 6).

Keywords Pubmed: Animals
Calcium Signaling/physiology*
Coronary Circulation/physiology*
DNA-Binding Proteins/deficiency
DNA-Binding Proteins/genetics
DNA-Binding Proteins/physiology*
Energy Metabolism
Gene Deletion
Gene Expression Regulation/physiology
Heart Function Tests
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Mice, Inbred C57BL
Mice, Knockout
Myocardial Contraction/physiology*
Myocytes, Cardiac/physiology*
Neovascularization, Physiologic/physiology
Nuclear Proteins/deficiency
Nuclear Proteins/genetics
Nuclear Proteins/physiology*
Oxygen Consumption
RNA, Messenger/biosynthesis
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors/deficiency
Transcription Factors/genetics
Transcription Factors/physiology*
Transcription, Genetic

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