Z Geburtshilfe Neonatol 2015; 219 - P09_5
DOI: 10.1055/s-0035-1566675

Heme Oxygenase-1 decreases soluble Fms-like tyrosine Kinase (sFlt-1) in human BeWo and HUVECs cells: role of Nrf2 signalling

N Kweider 1, U Pecks 2, 3, T Goecke 3, T Pufe 1, CJ Wruck 1, W Rath 3
  • 1Department of Anatomy and Cell Biology; Medical Faculty; RWTH Aachen University, Aachen, Germany
  • 2Department of Gynecology and Obstetrics, University Hospitals Schleswig-Holstein, Campus Kiel, Kiel, Germany
  • 3Department of Obstetrics and Gynecology, University Hospital of the RWTH, Aachen, Germany

Objectives: Oxidative stress of the placenta is considered to be the key intermediate step in the pathogenesis of preeclampsia (PE). The transcription factor Nrf2 regulates mainly the basal defence against oxidative stress. Nrf2 has been lately implicated to regulate angiogenesis via its target enzyme Heme oxygenase-1 (HO-1). We evaluated first the expression of both Nrf2 and HO-1 in placentae from early-onset preeclampsia cases. Then we examined in vitro the effect of Nrf2 activation on the expression of pro- and anti-angiogenic factors, VEGF and the soluble fms-like tyrosine kinase-1 (sFlt-1).

Methods: The protein levels of Nrf2 and HO-1 were evaluated in placentae of early-onset preeclamptic and healthy matched control women (29 – 33 weeks) (n = 9/groups) using western blot analysis.

In vitro: Using BeWo and the primary human umbilical vein endothelial cells (HUVECs) we tested the angiogenic effect of Nrf2 activation on these cells. ELISA, scratch- and tube formation-assays were mainly applied in this study.

Results: When compared to normal controls, HO-1 levels in preeclamptic placentas was decreased by 50% (P = 0.0418), whereas the Nrf2 levels shows no difference.

The activation of HO-1 via Nrf2 in vitro led to a significant increase in the protein levels of VEGF and a decrease in the augmented-sFlt-1 in the supernatant of the treated cells. Up-regulation of HO-1 enhanced tube formation and migration of the endothelial cells. This effect could be inhibited through haemoglobin, an inhibitor of HO activity.

Conclusion: Collectively, these data reveal a novel mechanism by which the decreased expression of HO-1 and its regulator Nrf2 in the placenta, during PE may involve in its pathogenesis. Activation of HO-1 through Nrf2 enhances trophoblasts proliferation and survival, induces angiogenesis and inhibits the release of the antiangiogenic factors. This may lay out the reason for considering Nrf2 as novel therapeutic target in preeclampsia.