Decreased Lectin-Like Oxidized LDL Receptor 1 (LOX-1) and Low Nrf2 Activation in Placenta Are Involved in Preeclampsia

Serum concentration of oxidized low-density lipoprotein (oxLDL) is higher in women with preeclampsia than in normal pregnant woman. Lectin-like oxLDL receptor-1 (LOX-1) is one of the scavenger receptors for oxLDL and is abundantly expressed in placenta. It is well known that oxLDL activates nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant and cytoprotective genes such as heme oxygenase-1 (HO-1), which play an important role in preeclampsia. However, it has yet to be elucidated whether LOX-1, along with Nrf2, participates in the pathology of preeclampsia. The objective of the study was to assess LOX-1 expression and Nrf2 activation in preeclamptic placentas and to manifest their physiological roles in preeclampsia. Expression and regulation of LOX-1, HO-1, and Nrf2 were evaluated by real-time quantitative RT-PCR and Western blotting. The functions of LOX-1 and Nrf2 were examined using an anti-LOX-1 antibody and Nrf2 activator in JAR, a choriocarcinoma cell line, and placental explants. Both LOX-1 expression and Nrf2 activation were significantly decreased in preeclamptic placentas compared with normal controls. A significant decrease in LOX-1 mRNA was found in placental explant cultures under hypoxic conditions. Activation of Nrf2 up-regulated HO-1 in both the JAR cells and placental explants. Furthermore, oxLDL increased HO-1 mRNA, whereas the blockade of LOX-1 inhibited the increase of HO-1 mRNA in JAR cells. Decreasing LOX-1 expression in preeclamptic placenta may contribute to high oxLDL concentration, low Nrf2 activation, and low HO-1 expression. These findings provide novel insights into the crucial role of LOX-1 and Nrf2 in the pathogenesis of preeclampsia.