Abstract P206: Novel Dual-function Redox Modulator Therapy For Preeclampsia

Abstract

Introduction: Preeclampsia is a hypertensive disorder of pregnancy which is associated with substantial morbidity for the mother and fetus. Reduced nitric oxide bioavailability and oxidative stress are key in the maternal and fetal pathophysiology of preeclampsia. Method: In this study, we assessed the potential therapeutic effect and mechanisms of action of a novel dual-function nitric oxide donor/redox modulator, AKT-1005, in an animal model of Ad.sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis. Ad.sFlt1-overexpressing CD1 mice were treated via minipump with AKT-1005 (20 mg/kg) or vehicle (n=15 per group). Results: Treatment with AKT-1005 for 7 days significantly reduced sFlt1-induced hypertension and endotheliosis of the kidney glomeruli. Kidney function was also assessed by cystatin C ELISA, which showed significant reduction in AKT-1005 treated mice compared to controls. AKT-1005 treatment increased NO bioavailabilty as assessed by Griess method. The increase of free plasma sEndoglin (anti-angiogenic factor) following Ad.sFlt-1 was ameliorated after treatment with AKT-1005. Similarly, sEndoglin expression in placental tissue was reduced in the AKT-1005 treated group, which correlated with improved placental histology, reduced oxidative stress and increased endothelial expression of CD31. Moreover, wire myography studies in female mesenteric vessels have shown vasodilating capacity of AKT-1005. Conclusion: Our findings suggest that AKT-1005 significantly extenuates the sFlt-1-induced preeclampsia phenotypes by inhibiting oxidative stress, anti-angiogenic response, and increasing NO bioavailability. Further studies are needed to assess safety and efficacy of this type of dual-function redox-modulator therapy in animal models. Additional research is warranted to investigate the role of AKT-1005 as a novel therapeutic agent for vascular disorders such as preeclampsia.