title: Oxidized LDL suppresses NF-kappaB and overcomes protection from apoptosis in activated endothelial cells.
abstract: Atherosclerosis is a chronic inflammatory disease associated with enhanced apoptotic cell death in vascular cells, partly induced by oxidized low-density lipoprotein (OxLDL). However, proinflammatory stimuli such as lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) activate endothelial cells (EC) and inhibit apoptosis through induction of nuclear factor kappaB (NF-kappaB)-dependent genes. This study therefore investigated whether OxLDL or its component, lysophosphatidylcholine (LPC), interacts with the effect of LPS or TNF-alpha on cell survival. Human EC were incubated with LPS, TNF-alpha, OxLDL, or LPC alone or in combinations. OxLDL (100 to 200 microg/ml) and LPC (100 to 300 microM) induced apoptosis dose-dependently. LPS and TNF-alpha had no effect on cell survival in the presence or absence of OxLDL or LPC. LPS and TNF-alpha both induced the antiapoptotic gene A20, whereas OxLDL and LPC suppressed its induction. Expression of A20 is regulated by NF-kappaB. OxLDL and LPC dose-dependently suppressed NF-kappaB activity. For functional analysis, bovine EC were transfected with A20 encoding expression constructs in sense and antisense orientation. Bovine EC that overexpressed A20 were protected against OxLDL-induced apoptosis, whereas expression of antisense A20 rendered cells more sensitive to OxLDL. These results suggest that OxLDL not only induces cell death, as has been shown before, but also compromises antiapoptotic protection of activated EC. OxLDL sensitizes EC to apoptotic triggers by interfering with the induction of A20 during the inflammatory response seen in atherosclerotic lesions. This inhibition is based on repression of NF-kappaB activation. The effect may be caused by the OxLDL component LPC.
authors.affiliation: University Hospital, Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Heermeier
authors.affiliation: University Hospital, Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Leicht
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Würzburg, Germany.
authors.forename: Alois
authors.initials: A
authors.lastname: Palmetshofer
authors.affiliation: University Hospital, Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Ullrich
authors.affiliation: University Hospital, Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.affiliation: University Hospital, Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Galle
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D002417:Cattle; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; C099252:oxidized low density lipoprotein; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3