Abstract P105: Redox Modulator Akt-1005 Alleviates Oxidant Stress In An In Vitro Model Of Preeclampsia

Abstract

Background: Preeclampsia (PE) is a pregnancy-specific syndrome affecting 5-7% of all pregnant women, and there is no effective treatment available. Early abnormal placental development is associated with oxidative stress and the release of reactive oxygen species in the placenta. This phenomenon leads to downstream signaling and production of anti-angiogenic factors, which cause endothelial and trophoblast dysfunction and the cardinal features of PE, i.e., hypertension, proteinuria, and in severe cases, eclampsia. Our group developed a novel series of redox modulators and sought to test if these compounds can effectively reduce placental oxidative stress and mitigate PE symptoms in vitro . Methods: We induced in vitro oxidant stress in human villous explants with 2% O 2 and assessed whether augmenting cell-redox function with the proposed compound AKT-1005 reduced (i) cell injury (cell cytotoxicity assay), (ii) mitochondrial stress (mitochondrial -derived superoxide production, mitochondria dysfunction) (iii) production of the transcription factor HIF1A and (iv) downstream anti-angiogenic responses (sFLT1 production). These effects were compared with reference antioxidants i.e., Vit C and MitoTEMPO. Results: In our villous explant assays, pretreatment with the AKT-1005 reduced mitochondrial-derived ROS production in hypoxia-exposed trophoblasts cells, indicating that the key factor in the development of PE, the oxidant stress, can be alleviated by the redox modulator compound. The AKT-1005 pretreatment also reduced HIF-1A expression and sFLT1 protein expression in hypoxia-exposed villous trophoblast cell, with better efficacy than Vit C and MitoTempo. Furthermore, AKT-1005 improved the mitochondrial electron chain enzyme activity in the stressed explant culture, mainly in syncytiotrophoblast cells, which is another promising characteristic of the applied antioxidant molecule. Conclusion: In reducing placental trophoblast oxidative stress, redox modulators present a potential novel therapeutic approach for the treatment of preeclampsia. Future investigation is warranted regarding the in vivo use of these compounds.