Abstract
The apoptotic effect of oxidized LDLs (oxLDLs) is mediated through a complex sequence of signaling events involving a deregulation of the cytosolic Ca2+ 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 Ca2+ 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.
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Abbreviations
- Apo:
-
apolipoprotein
- ATF:
-
activating transcription factor
- Bcl-2:
-
B-cell lymphoma 2
- BiP:
-
binding immunoglobulin protein
- CHOP:
-
C/EBP homologous protein
- EGTA, ethylene glycol-bis(βamino-ethylether)-N,N,N',N':
-
-tetraacetic acid
- eIF2α, eucaryotic translation initiation factor -2:
-
α subunit
- ER:
-
endoplasmic reticulum
- ERAD:
-
endoplasmic reticulum associated degradation
- GRP78:
-
78-kDa glucose-regulated protein
- HDL:
-
high-density lipoprotein
- HMEC-1:
-
human microvascular endothelial cell-1
- IRE1α:
-
Inositol-requiring kinase 1 α
- JNK:
-
c-Jun N-terminal kinase
- KDEL, ER retention peptide KDEL (i. e.,:
-
Lys Asp Glu Leu)
- LC3:
-
microtubule-associated protein-1 light-chain 3
- 3-MA:
-
3-methyladenine
- MEF:
-
mouse embryonic fibroblasts
- mTOR:
-
mammalian target of rapamycin
- MTT, 3-(4,5-dimethylthiazol-2-yl)-2:
-
5-diphenyltetrazolium bromide
- NF-KB:
-
nuclear factor-κB
- oxLDLs:
-
oxidized Low-density lipoproteins
- PERK:
-
PKR (protein kinase regulated by RNA) like endoplasmic reticulum Kinase
- PI:
-
propidium iodide
- PS:
-
phosphatidylserine
- siRNA:
-
small interfering RNA
- TRAF2:
-
TNF receptor-associated factor 2
- TRPC1:
-
transient receptor potential canonical channel 1
- UPR:
-
unfolded protein response
- XBP1s:
-
X-box-binding protein 1 spliced form
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Acknowledgements
This work was supported by Institut National de la Santé et de la Recherche Médicale, Université Toulouse-3, la ‘Fondation Cœur et Artères’ no FCA06T6, et la Fondation pour la Recherche Médicale, no DCV2007040927. CM is a recipient of a ‘Fondation pour la Recherche Medicale’ fellowship. We acknowledge JC Thiers and C Bernis for their excellent technical assistance. We are grateful to Prof. D Ron for providing MEFs CHOP-/- and wild-type cells and Dr. V Gallet (SNCF Laboratory, Toulouse) for providing human serum.
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Muller, C., Salvayre, R., Nègre-Salvayre, A. et al. HDLs inhibit endoplasmic reticulum stress and autophagic response induced by oxidized LDLs. Cell Death Differ 18, 817–828 (2011). https://doi.org/10.1038/cdd.2010.149
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DOI: https://doi.org/10.1038/cdd.2010.149
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