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ORIGINAL RESEARCH ARTICLE

Heart HIF-1 and MAP Kinases During Hypoxia: Are They Associated In Vivo?

Anna Caretti^*,1, Sandrine Morel^,1, Giuseppina Milano, Monica Fantacci^*, Paola Bianciardi^*, Raffaella Ronchi^*, Giuseppe Vassalli, Ludwig K. von Segesser and Michele Samaja^*,2

^* Department of Medicine, Surgery, and Dentistry, University of Milan, San Paolo Hospital, Milan I-20142, Italy; and Centre Hospitalier Universitaire Vaudois, 1005 Lausanne, Switzerland

To whom requests for reprints should be addressed at ² University of Milan, San Paolo Hospital, via di Rudinì 8, I-20142 Milan, Italy. E-mail: Michele.Samaja{at}unimi.it

To study the in vivo dynamics of hypoxia-inducible factor 1 (HIF-1), master regulator of O₂-dependent gene expression, and mitogen-activated protein kinases (MAPKs) in the hypoxic myocardium, Sprague-Dawley rats (n = 4 to 6 per group) were exposed to 1-hr hypoxia (10% O₂), 23-hr hypoxia, and 23-hr hypoxia, followed by reoxygenation. HIF-1 increased 15-fold after 1-hr hypoxia, remained constant for 23 hrs, and returned to baseline on reoxygenation. Extracellular signal–regulated kinases (ERK1/2) were unchanged throughout. Phosphorylated p38 increased 4-fold after 1-hr hypoxia and returned to baseline within 23-hr hypoxia. The activity of stress-activated protein kinases/c-Jun NH₂-terminal kinases (JNKs), measured as phosphorylated c-Jun, increased 3-fold after 1-hr hypoxia and remained sustained afterward. Furthermore, HIF-1 was halved in rats that were administered with the p38 inhibitor SB202190 and made hypoxic for 1 hr. In conclusion, although very sensitive to the reoxygenation, HIF-1 is overexpressed in vivo in the hypoxic myocardium, and its acute induction by hypoxia is correlated with that of p38.

Key Words: p38 • JNK • ERK1/2 • SB202190 • c-Jun • HSP27

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