[279-POS]: Potential therapeutic value of the heme oxygenase system in preeclampsia.

OBJECTIVES: Despite intensive research, little in the way of new therapeutics has been developed for the preeclampsia patient. Several in vitro reports have suggested that heme oxygenase (HO) and its metabolic byproducts could inhibit known pathological pathways active in preeclampsia; specifically sFlt-1 production, oxidative stress, and innate immune activation. Here, we investigated the potential of HO induction, or the administration of its metabolic byproducts carbon monoxide and bilirubin, to act as a palliative in preclinical models of pregnancy-induced hypertension and preeclampsia.

METHODS: We utilized the rodent Reduced Uterine Perfusion Pressure (RUPP) model of placental ischemia-induced hypertension to assess the effects of HO induction by cobalt protoporphyrin (5mg/kg i.p.) as well as the effects of a CO donor molecule (CORM-A1, 5mg/kg/day i.v.) and bilirubin (30mg/kg/q 48h, i.p.). The effects of HO induction were also determined in both the sFlt-1 infusion model (7.4μg/kg/day GD14-19) and TNF-α (50ng/day GD14-19). On GD19, maternal blood pressure was measured via carotid catheter and tissues were collected for analysis. sFlt-1 and VEGF were measured via ELISA, placental ROS was measured via lucigenin chemilluminescence, and vascular production of endothelin-1 was assayed via qRT-PCR. The direct effects of HO and its metabolites on hypoxia-induced sFlt-1 and ROS production were also determined directly in placental explants ex vivo.

RESULTS: RUPP induced hypertension was significantly attenuated by HO induction and administration of either CO or bilirubin. In addition, HO induction was associated with normalization of sFlt-1/VEGF balance, placental oxidative stress, and vascular production of endothelin-1 in both RUPP and sFlt-1 induced hypertension. Further, HO induction significantly attenuated both sFlt-1 and TNF-α induced hypertension. HO and its individual metabolites were shown to inhibit hypoxia-induced production of sFlt-1 and superoxide.

CONCLUSIONS: Pharmacological induction of HO or administration of its metabolites could be a useful therapeutic approach for the management of preeclampsia.

DISCLOSURES: E.M. George: None. J.P. Granger: None.