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Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1-Mediated Autophagy in Human Granulosa Cells as an Alternative of Programmed Cell Death

Institute of Anatomy (N.D., O.Z., M.N., A.R., K.S.-B.), University of Leipzig, D-04103 Leipzig, Germany; Centre for Reproductive Medicine (F.A.H., V.B.), Leipzig, Germany; and Fraunhofer Institute of Toxicology and Experimental Medicine (J.B.), Center for Drug Research and Medical Biotechnology, D-30625 Hannover, Germany

Address all correspondence and requests for reprints to: Katharina Spanel-Borowski, Institute of Anatomy, University of Leipzig, Liebigstrasse 13, D-04103 Leipzig, Germany. E-mail: spanelb{at}medizin.uni-leipzig.de.

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 -carrageenan) abrogated the up-regulation of LOX-1. The oxLDL (100 µg/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.

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