Heme oxygenase‐1 attenuates hypoxia‐induced superoxide production in placental villi

Preeclampsia is a hypertensive disorder of pregnancy which affects ~5–10% of all women and is a leading cause of maternal and fetal morbidity. Recent research has demonstrated that a central causative factor is placental ischemia and hypoxia. The ischemic placenta releases vasoactive factors which then cause the symptomatic manifestations of the disorder, one of which being superoxide. One potential therapeutic target which has been suggested for the treatment of preeclampsia is the protein Heme Oxygenase‐1 (HO‐1), which in vitro negatively regulates both the vasoactive peptides and produces bilirubin, a known antioxidant. The purpose of this study was to determine whether HO‐1 attenuates hypoxia‐Induced superoxide production in placental villi. Placental villi exposed to hypoxic conditions for 48hr in vitro demonstrated a ~70% increase in the production of superoxide, as measured by DHE fluorescence. Pharmacological induction of HO‐1 slightly decreased (~18%) superoxide production in normal oxygen, and completely normalized superoxide levels during hypoxia. Furthermore, incubation of the HO‐1 metabolite bilirubin dramatically reduced superoxide in both normoxic (~60%) and hypoxic (~46%) villi, supporting HO‐1 as a therapeutic target for treatment of preeclampsia. Support for this work was provided by NIH grants HL51971 and T32 HL105324‐01.