HDLs inhibit endoplasmic reticulum stress and autophagic response induced by oxidized LDLs.
The apoptotic effect of oxidized LDLs (oxLDLs) is mediated through a complex sequence of signaling events involving a deregulation of the cytosolic Ca(2+) homeostasis. OxLDLs also trigger ER stress that may lead to cellular dysfunction and apoptosis, through the activation of the IRE1α/c-Jun N-terminal kinase pathway. Moreover, ER stress and oxidized lipids have been shown to trigger autophagy. The antiatherogenic high-density lipoproteins (HDLs) display protective effects against oxLDLs toxicity. To more deeply investigate the mechanisms mediating the protective effects of HDLs, we examined whether ER stress and autophagy were implicated in oxLDLs-induced apoptosis and whether HDLs prevented these stress processes. We report that, in human endothelial cells, HDLs prevent the oxLDL-induced activation of the ER stress sensors IRE1α, eIF2α and ATF6 and subsequent activation of the proapoptotic mediators JNK and CHOP. OxLDLs also trigger the activation of autophagy, as assessed by LC3 processing and Beclin-1 expression. The autophagic process is independent of the proapoptotic arms of ER stress, but Beclin-1 contributes to PS exposure and subsequent phagocytosis of oxLDLs exposed cells. Induction of autophagy and PS exposure by oxLDLs is prevented by HDLs. Finally, the cytosolic Ca(2+) deregulation triggered by oxLDLs is a common signaling pathway that mediates ER stress-induced cell death and autophagy, all these events being blocked by HDLs.
INSERM U-858, Department of Vascular Biology, IFR-150, CHU Rangueil, Toulouse, France.
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C
Muller
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Salvayre
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Nègre-Salvayre
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Vindis
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D015415:Biomarkers / Q000378:metabolism; D020013:Calcium Signaling; D053454:Caspase 12 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000494:pharmacology / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000494:pharmacology / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010587:Phagocytosis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D015415:Biomarkers; C497249:DDIT3 protein, human; D015852:Eukaryotic Initiation Factor-2; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C099252:oxidized low density lipoprotein; D051742:Transcription Factor CHOP; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases; C506440:Casp12 protein, mouse; D053454:Caspase 12