Hypoxia-inducible factor (HIF) regulates expression of genes involved in adaptation to
hypoxia and
ischemia. Three
prolyl hydroxylases (PHD1-3) underlie
oxygen-regulated destruction of HIFalpha chains. We have investigated the organ distribution of the PHDs in the rat, their regulation by
hypoxia and changes in local expression after experimental
myocardial infarction using
RNase protection assays, in situ hybridization and immunohistochemistry. mRNAs of all
isoforms were detectable in heart, liver, kidney, brain, testis and lung. In normal animals, highest levels for PHD2
mRNA and PHD3
mRNA were found in myocardium, whereas PHD1
mRNA was detected predominantly in the testis. PHD1
mRNA was constitutively expressed. PHD2
mRNA was induced by
hypoxia in the liver and PHD3
mRNA in liver, testis and heart. Overall our results show that PHD2
mRNA is ubiquitously expressed in normal animals, in keeping with a general role in
oxygen sensing. PHD1 and 3
mRNA distributions suggest particular roles in testis and heart, respectively. In a model of
myocardial infarction, in situ hybridization showed periischemic enhancement for PHD2
mRNA and PHD3
mRNA, but not PHD1
mRNA. Immunostaining of PHD2 and 3 in infarcted hearts showed enhanced
protein expression, maximal 7 days after
infarction. Levels were strongest in regions neighboring areas of HIF staining but also partially overlapped with these zones. Inducibility of PHD2 and 3 by
hypoxia and
ischemia in vivo has important implications both for the pathophysiology of conditions where
oxygen supply is deranged and for attempts to manipulate the HIF system therapeutically.