The Study Of Hypoxia-inducible Transcription Factors In The Placenta With Intrahepatic Cholestasis Of Pregnancy

[Objectives] Intrahepatic cholestasis of pregnancy (ICP) is a disease that occurs during the second half of pregnancy and dose greate harm to the fetus. The molecular mechanisms of fetal hypoxia signaling in ICP are virtually unexplored. As a key transcriptional regulator of downstream genes, hypoxia-inducible transcription factor (HIF) is a basic helix-loop-helix transcription factor which transactivates downstream molecules responses to hypoxia. Therefore, we investigated the expression of the HIF in placenta of pregnant women with ICP. [Methods] 20 placental samples of pregnant women with ICP and 20 normal term placental samples were investigated the expression of HIF-1α and -2α mRNA by RT-PCR. Protein from villous explant culture under hypoxia condition (n=8each) was probed for HIF-1α, HIF-2α and P53 by immuno-histochemistry methods. [Results] 1. The expression of HIF-la and -2a mRNA in two groups had no significant difference (P>0.05). 2.Under normal concentration oxygen HIF-2α and P53 were highly expressed in the placentae of pregnant women with ICP (p<0.01), whereas the HIF-1α expression was normal compared to those normal term placentae. 3. HIF and P53 proteins in the placental villoustissues cultured for 4h under hypoxic condition (2%O2) were detected in two groups. The expressions of HIF-la and P53 proteins increased in the placentae of pregnant women with ICP (p<0.05 and p<0.001 respectively), but the HIF-2a expression kept unchangeable. 4. The HIF-la and -2a proteins were assessed during subsequent oxygenation over 60 minutes (21%O2). The high oxygen concentration decreased the expression of both HIF-la in 30 minutes (p<0.05) and HIF-2a in 60 minutes (p<0.05). HIF-la was lower expressed in the placentae of pregnant women with ICP (p<0.05) in 60 minutes, whereas HIF-2a was highly expressed (p<0.01) .5. The hypoxic/nonhypoxic ratio of P53 was highly changed(P<0.01) in ICP. There was a positive correlation between P53 and HIF-la in ICP(PO.Ol). [conclusions] Under hypoxic conditions high increase of HIF-la may influence the increase of P53 directly, which may be one of the hypoxia pathogenesis factors in ICP. The fetal hypoxia and stillbirth may be the results of unbalance of HIF-la and P53 which induced apoptosis in hypoxia.