Decreased lectin-like oxidized LDL receptor 1 (LOX-1) and low Nrf2 activation in placenta are involved in preeclampsia.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
Yoshitsugu
Y
Chigusa
Keiji
K
Tatsumi
Eiji
E
Kondoh
Kohei
K
Fujita
Fumitomo
F
Nishimura
Haruta
H
Mogami
Ikuo
I
Konishi
D000328:Adult; D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D002822:Choriocarcinoma; D002824:Chorionic Villi / Q000378:metabolism / Q000473:pathology; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D014594:Uterine Neoplasms
D000975:Antioxidants; D008077:Lipoproteins, LDL; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495137:OLR1 protein, human; D012333:RNA, Messenger; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1