CYP4A11/20-HETE induces oxidative stress and inhibits trophoblast proliferation via the PI3K/AKT signaling pathway during preeclampsia

Background: Placental oxidative stress injury is considered to be a key cause of preeclampsia, but the specific molecules that regulate the balance between oxidant and antioxidant levels remain unclear. 20-Hydroxyeicosatetraenoic acid (20-HETE), an important cytochrome P450 family 4 subfamily A polypeptide 11 (CYP4A11)-dependent eicosanoids, has been proved to increase reactive oxygen species production. Whether CYP4A11/20-HETE is involved in the regulation of oxidant or antioxidant levels in preeclamptic placenta is worth exploring. Methods: The expressions of CYP4A11/20-HETE and redox related agents in placentas from pregnant women with and without preeclampsia were compared. Cellular lentiviral transfection was used to assess the effect of altered CYP4A11/20-HETE metabolism on oxidative stress and proliferation of trophoblasts, and RNA sequencing was taken to search its underlying mechanisms. Besides, in vivo animal experiments were arranged to verify whether Cyp4a10 (a protein that is highly homologous to human CYP4A11) overloaded lentivirus could induce preeclampsia-like symptoms in pregnant mice. Results: The levels of CYP4A11/20-HETE were elevated in placentas from preeclamptic patients, and its expression was strongly associated with the expression of oxidative stress-related genes in the placentas. In vitro , CYP4A11/20-HETE overexpression caused oxidative stress injury and inhibited the proliferation of trophoblasts by suppressing the PI3K/AKT signaling pathway, and these effects were ameliorated by the pretreatment with the PI3K agonist 740 Y-P. In vivo , upregulation of Cyp4a10 (a protein that is highly homologous to human CYP4A11) during the placentation period caused hypertension and proteinuria in pregnant mice, presumably by impairing the placental antioxidant capacity and disrupting trophoblast proliferation. Conclusion: This study identified CYP4A11/20-HETE as a potential causative factor of preeclampsia, which provide new insights into the pathogenesis of preeclampsia and may open a novel chapter for the future treatment strategies of preeclampsia.