Overexpressed HO-1 is associated with reduced STAT3 activation in preeclampsia placenta and inhibits STAT3 phosphorylation in placental JEG-3 cells under hypoxia

INTRODUCTION: Inadequate trophoblast invasion and placentation are widely believed to contribute to preeclampsia, and multiple lines of evidence indicate the involvement of hypoxia in preeclampsia. However, the molecular mechanisms underlying the association of placental hypoxia with preeclampsia are not clear. MATERIAL AND METHODS: The present study focused on the role in preeclampsia of heme oxygenase 1 (HO-1), which is an inducible isoform of HO in response to hypoxia, via examining the expression of HO-1 and the expression and phosphorylation (Tyr705) of Signal transducer and activator of transcription (STAT) 3 in preeclamptic placentas via the immunohistochemical method, western blotting assay and RT-qPCR method. Then we investigated the regulation by HO-1 of the expression and phosphorylation of STAT3 in human placental choriocarcinoma JEG-3 cells under hypoxia. RESULTS: There was upregulation of HO-1 at both mRNA (1.506 ±0.08347 (N = 37) vs. 1.000 ±0.08854 (N = 31), p < 0.0001) and protein (0.630 ±0.155 (N = 35) vs. 0.310 ±0.052, 0.630 ±0.155 (N = 35), p < 0.001) levels and a reduced level of STAT3 phosphorylation (Tyr 705) in the preeclamptic placental tissues, compared to normal placental tissues (0.143 ±0.027 (N = 35) vs. 0.194 ±0.028 (N = 35), p < 0.01). Also, in vitro experiments demonstrated that HO-1 was markedly promoted by hypoxia in human placental choriocarcinoma JEG-3 cells, 6 or 12 h post treatment (p < 0.05 or p < 0.01). However, the STAT3 phosphorylation (Tyr 705) was attenuated by sustained hypoxia (p < 0.01). Moreover, it was demonstrated that HO-1 overexpression significantly inhibited the hypoxia-promoted STAT3 phosphorylation (Tyr 705). CONCLUSIONS: HO-1 was overexpressed in PE placenta, in association with reduced STAT3 phosphorylation (Tyr 705). HO-1 inhibits the STAT3 phosphorylation in placental JEG-3 cells under hypoxia. Thus, we speculate that overexpressed HO-1 might contribute to the reduced STAT3 phosphorylation (Tyr 705) and the pathogenesis of preeclampsia.