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Hypoxia inducible factor regulates the cardiac expression and secretion of apelin

Veli-Pekka Ronkainen^*, Jarkko J. Ronkainen^*, Sandra L. Hänninen^*, Hanna Leskinen, Jorge L. Ruas, Teresa Pereira, Lorenz Poellinger, Olli Vuolteenaho^* and Pasi Tavi^*,1

^* Department of Physiology, and

Department of Pharmacology and Toxicology, University of Oulu and Biocenter Oulu, Finland; and

Department of Cell and Molecular Biology, Karolinska Institutet, S-171 77, Stockholm, Sweden

¹Correspondence: University of Oulu, Department of Physiology, PO Box 5000, 90014-University of Oulu, Finland. E-mail: pasi.tavi{at}oulu.fi

Apelin and its G-protein-coupled receptor APJ have various beneficial effects on cardiac function and blood pressure. The mechanisms that regulate apelin gene expression are not known. Because apelin gene expression has been shown to increase in cardiac ischemia, we investigated if apelin (Apln) gene expression was sensitive to hypoxia. Here we show that hypoxia increases the apelin expression in rat myocardium and in cultured cardiomyocytes. Pharmacological activation of hypoxia inducible factor by desferrioxamine (DFO) or expression of a constitutively active form of HIF-1 increased apelin expression in cardiomyocyte cultures. The induction of apelin by hypoxia was abolished on transient expression of the HIF inhibitory PAS protein in cardiomyocytes. Increased apelin expression induced by hypoxia or DFO was accompanied by the processing of the cellular storage form proapelin into smaller apelin peptides and increased secretion of these biologically active forms of apelin. In a rat in vivo model, acute myocardial infarction (24 h) led to a transient increase in ventricular apelin mRNA levels. Our results indicate that apelin gene is regulated by hypoxia in cardiac myocytes via the HIF pathway, suggesting a role for apelin as a potential marker for acute cardiac hypoxia with a possible compensatory role in myocardial tissue suffering from oxygen deprivation.—Ronkainen, V.-P., Ronkainen, J. J., Hänninen, S. L., Leskinen, H., Ruas, J. L., Pereira, T., Poellinger, L., Vuolteenaho, O., Tavi, P. Hypoxia inducible factor regulates the cardiac expression and secretion of apelin.

Key Words: hormones • infarction • ischemia • HIF

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