Targeted antioxidant treatment in the placenta: a superoxide dismutase mimic plus catalase rescues trophoblast growth after oxidative challenge

Abstract

Objectives: Placental oxidative stress may be important in the patho-genesis of preeclampsia, and we have previously found placental mito-chondrial and antioxidant adaptations in mild preeclampsia that mayallow these pregnancies to reach term delivery. However, clinical trials ofantioxidant treatments have been generally unsuccessful. Superoxidedismutase (SOD) converts superoxide to hydrogen peroxide (H2O2), whichis then converted to water and oxygen by catalase, forming a completesystem for the detoxification of reactive oxygen species (ROS) that may bea therapeutic target. Methods: Placental tissue was collected from preeclamptic (term n¼10,pre-term n¼6) and matched control pregnancies (term n¼10, pre-termn¼6). Gene expression was determined by qPCR. SOD activity wasmeasured in total and mitochondrial protein. Swan71 trophoblasts weretreated with the SOD mimetic MnTMPyP, catalase, and the mitochondrialinhibitor rotenone, and H2O2production and cell growth monitored. Results: In pre-term preeclamptic placentae,SOD1was downregulated(p¼0.048), and there was a reduction in total SOD activity (p¼0.045).Expression of mitochondrial-targetedSOD2was not changed; however,pre-term preeclamptic placentae had reduced mitochondrial SOD activity(p¼0.029). There were no changes in markers of SOD function in termpreeclamptic placentae. Treatment with MnTMPyP plus catalase reducedrotenone-induced H2O2production (4 hours: p¼0.001) and attenuated cellgrowth repression (10 hours: p¼0.001; 24 hours: p¼0.014). However,MnTMPyP without catalase repressed cell growth (10 hours: p¼0.004; 24hours: p¼0.002).Conclusion: SOD function was reduced in pre-term preeclampticplacentae but not those that reached term, indicating this may be a ther-apeutic target for extension of gestation.In vitrotreatment with the SODmimetic MnTMPyP plus catalase was effective in countering oxidativestress. The beneficial effect of MnTmPyP appears related to processingsuperoxide to H2O2, and requires the presence of catalase to fully detoxifyROS. Therefore, targeting relevant antioxidant systems may be critical totreatment outcomesNo Full Tex