Lectin-like oxidized low-density lipoprotein receptor-1-mediated autophagy in human granulosa cells as an alternative of programmed cell death.
The LOX-1 receptor, identified on endothelial cells, mediates the uptake of oxidized low-density lipoprotein (oxLDL). The oxLDL-dependent LOX-1 activation causes endothelial cell apoptosis. We here investigated the presence of LOX-1 in granulosa cells from patients under in vitro fertilization therapy. We were interested in the oxLDL-dependent LOX-1 receptor biology, in particular in the induction of apoptosis. In the human ovary, LOX-1 was localized in regressing antral follicles. In granulosa cell cultures, oxLDL-induced mRNA expression of LOX-1 in a time- and dose-dependent manner. The LOX-1 inhibitors (anti-LOX-1 antibody and kappa-carrageenan) abrogated the up-regulation of LOX-1. The oxLDL (100 microg/ml) treatment caused the autophagy form of programmed cell death: 1) reorganization of the actin cytoskeleton at the 6-h time point; 2) uptake of YO-PRO, a marker for the early step of programmed cell death, before propidium iodide staining to signify necrosis; 3) absence of apoptotic bodies and cleaved caspase-3; 4) abundant vacuole formation at the ultrastructural level; and 5) decrease of the autophagosome marker protein MAP LC3-I at the 6-h time point indicative of autophagosome formation. We conclude that follicular atresia is not under the exclusive control of apoptosis. The LOX-1-dependent autophagy represents an alternate form of programmed cell death. Obese women with high blood levels of oxLDL may display an increased rate of autophagic granulosa cell death.
Duerrschmidt
Nicole
N
Institute of Anatomy, University of Leipzig, Liebigstrasse 13, D-04103 Leipzig, Germany.
Zabirnyk
Olga
O
Nowicki
Marcin
M
Ricken
Albert
A
Hmeidan
Fayez A
FA
Blumenauer
Verona
V
Borlak
Jürgen
J
Spanel-Borowski
Katharina
K
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005496:Follicular Atresia / Q000378:metabolism; D006107:Granulosa Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007247:Infertility, Female / Q000378:metabolism / Q000473:pathology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology
D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D019311:Staurosporine