Heart HIF-1alpha and MAP kinases during hypoxia: are they associated in vivo?
To study the in vivo dynamics of hypoxia-inducible factor 1alpha (HIF-1alpha), master regulator of O(2)-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% O(2)), 23-hr hypoxia, and 23-hr hypoxia, followed by reoxygenation. HIF-1alpha 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 NH(2)-terminal kinases (JNKs), measured as phosphorylated c-Jun, increased 3-fold after 1-hr hypoxia and remained sustained afterward. Furthermore, HIF-1alpha 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-1alpha is overexpressed in vivo in the hypoxic myocardium, and its acute induction by hypoxia is correlated with that of p38.
Caretti
Anna
A
Department of Medicine, University of Milan, San Paolo Hospital, Milan, Italy.
Morel
Sandrine
S
Milano
Giuseppina
G
Fantacci
Monica
M
Bianciardi
Paola
P
Ronchi
Raffaella
R
Vassalli
Giuseppe
G
von Segesser
Ludwig K
LK
Samaja
Michele
M
D000818:Animals; D003600:Cytosol / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D010100:Oxygen