Published online before print December 23, 2008, doi: 10.1161/CIRCRESAHA.108.183749
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© 2009 American Heart Association, Inc.
Molecular Medicine |
Oxidized Low-Density Lipoproteins Trigger Endoplasmic Reticulum Stress in Vascular Cells
Prevention by Oxygen-Regulated Protein 150 Expression
From Institut National de la Santé et de la Recherche Médicale (M.S., N.A., C.V., C.M., J.-C.T., M.-A.M., R.S., A.N.-S.), U-858, Vascular Biology Department, IFR-31, Toulouse, France; Faculty of Medicine-Rangueil, Biochemistry and Molecular Biology Laboratory (J.-C.T., R.S., A.N.-S.), University of Toulouse, France; Department of Anatomy (Y.B.), Asahikawa Medical College Hokkaido, Japan; Division of Pathology (K.Z.), University of Zagreb and Clinical Hospital Centre, Croatia; and Department of Surgery (Y.S.), Division of Cardiovascular Surgery, Graduate School of Medicine, University of Osaka, Japan.
Correspondence to Dr A. Negre-Salvayre, Biochimie, INSERM U858, Eq10, IFR-31, CHU Rangueil, 1, avenue Jean Poulhès, BP84225-31432, Toulouse Cedex 4, France. E-mail anne.negre-salvayre{at}inserm.fr
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Abstract |
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Oxidized low-density lipoproteins (oxLDLs) trigger various biological responses potentially involved in atherogenesis. Disturbing endoplasmic reticulum (ER) function results in ER stress and unfolded protein response, which tends to restore ER homeostasis but switches to apoptosis when ER stress is prolonged. We aimed to investigate whether ER stress is induced by oxLDLs and can be prevented by the ER-associated chaperone ORP150 (150-kDa oxygen-regulated protein). oxLDLs and the lipid oxidation products 7-ketocholesterol and 4-hydroxynonenal induce ER stress in human endothelial cells (HMEC-1), characterized by the activation of ER stress sensors (phosphorylation of Ire1
and PERK, nuclear translocation of ATF6) and of their subsequent pathways (eukaryotic initiation factor 2 phosphorylation, expression of XBP1/spliced XBP1, CHOP, and KDEL chaperones GRP78, GRP94, ORP150). ER stress was inhibited by the antioxidant N-acetylcysteine. In advanced atherosclerotic lesions, phospho-Ire1, KDEL, and ORP150 staining were localized in lipid-rich areas with 4-hydroxynonenal adducts and CD68-positive macrophagic cells. By comparison, staining for 4-hydroxynonenal, phospho-Ire1, KDEL, and ORP were faint and more diffuse in intimal hyperplasia. ER stress takes part in the apoptotic effect of oxLDLs, through the Ire1/c-Jun N-terminal kinase pathway, as assessed by the protective effect of specific small interfering RNAs and c-Jun N-terminal kinase inhibitor. Forced expression of the chaperone ORP150 reduced both oxLDL-induced ER stress and apoptosis. ER stress markers and ORP150 chaperone are expressed in areas containing oxLDLs in atherosclerotic lesions and are induced by oxLDLs and oxidized lipids in cultured cells. The forced expression of ORP150 highlights its new protective role against oxLDL-induced ER stress and subsequent apoptosis.
Key Words: ER stress • apoptosis • ORP150 • oxidized LDL • atherosclerosis
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Low oxidized low-density lipoprotein (oxLDL) concentration exhibit proinflammatory and mitogenic effects, whereas higher concentrations elicit a progressive inhibition of survival mechanisms and the induction of proapoptotic signaling pathways.1–5 oxLDLs may alter the fragile balance between survival and death of vascular cells, thereby leading to stable-to-vulnerable plaque transition and finally to atherothrombotic events.6–8
The stress of the endoplasmic reticulum (ER) occurs in atherosclerotic lesions of hypercholesterolemic (apolipoprotein [apo]E–/–) mice,9 and could be associated with acute coronary syndrome.10 ER stress emerges as a new adaptive system determining the fate of cells to survive or die11 and may thereby be implicated in the erosion or rupture of atherosclerotic plaques.
Altered protein folding and ER stress occurs in various pathological conditions, including ischemia, hypoxia, heat shock, proteasome inhibition, glycosylation inhibition, oxidative stress, and calcium depletion of ER stores.12,13 The accumulation of unfolded protein aggregates leads to the activation of transmembrane sensors/transducers inositol-requiring enzyme (Ire)1, PERK (RNA-dependent protein kinase–like endoplasmic reticulum kinase), and activating transcription factor (ATF)6 that regulate several signaling pathways, gene expression, and protein synthesis.11
The presence of ER-resident chaperones is crucial for facilitating and maintaining the protein folding, thereby preventing ER stress and promoting cell survival.14–17 GRP78/BiP, the best characterized ER-resident chaperone, plays a central role in regulating ER stress via its ability to control the activation of transmembrane ER stress sensors/transducers, through a binding–release mechanism.18 On ER stress induction, GRP78/BiP binds misfolded proteins, thereby releasing the ER stress sensors that become activated, leading to the unfolded protein response (UPR). UPR triggers adaptive responses to ER dysfunction,11,19 and switches to apoptosis in case of prolonged or severe ER stress.20–22
The antiapoptotic ER-associated chaperone ORP150 (150-kDa oxygen-regulated protein) is induced by hypoxia and oxidative stress.23–25 The mechanism of protection evoked by ORP150 could include an inhibition of calcium mobilization from ER.26,27 The interactions between ORP150 and ER stress are not yet clarified.
This led us to investigate whether induction of ER stress by oxLDLs is implicated in oxLDL-induced apoptosis of vascular cells and whether expression of the ER resident chaperone protein ORP150 may prevent oxLDL-induced ER stress and apoptosis.
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Materials and Methods |
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Human LDLs (1.019_d_1.063) were isolated by sequential ultracentrifugation and oxidized by UV/copper irradiation.4,5 We used human microvascular endothelial cells (HMEC-1) (Dr Candal, Centers for Disease Control and Prevention, Atlanta, Ga), wild-type or transfected with a ORP150 sense plasmid.27 The following methods were used: immunocytochemistry, immunoprecipitation, Western blot analysis, knockdown of protein by small interfering (si)RNA transfection, MTT viability test, and DEVDase activity. Human arteries obtained from vascular surgery and carotid endarterectomy were used for immunohistochemistry or Western blot analysis. Statistical analysis was performed by ANOVA (Tukey test; SigmaStat).
An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournals.org.
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Results |
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oxLDLs Induce the Activation of ER Stress in HMEC-1 Cells
ER stress is characterized by the activation of ER stress sensors, leading to UPR induction and expression of ER-resident proteins bearing the unique C-terminal sequence KDEL.18
Incubation of HMEC-1 cells with mildly oxLDLs (200 µg apoB/mL) induced a time-dependent activation of the ER stress transducers, as assessed by the phosphorylation of PERK and Ire1 (Figure 1A and 1B). Moreover, the detection of ATF6 in the nucleus of cells treated with oxLDLs is indicative of the cleavage of ATF6 by site 1 and site 2 proteases, allowing the release of its cytosolic domain and its nuclear translocation (Figure 1C). Consistent with the activation of ATF6, oxLDLs induced a time-dependent expression of the proapoptotic factor CHOP mRNA (Figure 2A and 2B) and of XBP1 mRNA and its spliced form (sXBP1) (Figure 2C and 2D). As expected, PERK activated by oxLDLs, in turn, induced the phosphorylation of its substrate eukaryotic initiation factor (eIF)2 (Figure 2E), which is known to inhibit the general pathway of protein biosynthesis. Finally, oxLDLs induced the expression of the KDEL motif–bearing ER chaperones at 150 kDa (ORP150), 94 kDa (GRP94), and 78 kDa (GRP78/BiP) (Figure 2F). It may be noted that similar results were observed with cell-oxidized LDL (data not shown), but we have chosen to use UV/copper oxLDLs to avoid interference by bioactive compounds potentially emitted from the cells used for LDL oxidation.
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Altogether, these data indicate that oxLDLs activate the 3 pathways of ER stress, which lead concomitantly to the activation of proapoptotic mediators (CHOP) and the expression of protective ER chaperones.
ER Stress Markers in Atherosclerotic Lesions
Because oxLDLs (and oxidized lipids) are present in atherosclerotic lesions,28 we investigated whether the expression of UPR markers, such as phospho-Ire1 and KDEL motif–bearing cells, is increased in human atherosclerotic lesions of carotid endarterectomy and in aortas obtained at autopsy. As shown in Figure 3, staining for phospho-Ire1 (pIre1) and KDEL were markedly increased in the core area of advanced atherosclerotic lesions from carotid endarterectomy, in agreement with Zhou et al.9 These markers were faintly expressed in stable aortic plaques, whereas they were not detected in normal mammary artery. Interestingly, ER stress markers were expressed in the same area as the lipid peroxidation marker 4-hydroxynonenal (4-HNE) (Figure I in the online supplement data supplement). It may be noted that in advanced plaques, 4-HNE was localized mainly in the lipid core, labeled by CD68, a marker of macrophages. In contrast, -actin–positive smooth muscle cells were located in the surroundings of the central core, and expressed no (or only slightly) ER stress markers.
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These data suggest that lipid peroxidation markers and ER stress/UPR markers are present in the same area within the lesions, thus suggesting that oxLDLs (and oxidized lipids) may contribute to ER stress induction, in agreement with the data reported for oxysterols by Myoishi et al.10
4-HNE and 7-Ketocholesterol Trigger ER Stress
Because 4-HNE is a component of oxLDLs and is found in atherosclerotic lesions, like ER stress markers, we investigated whether it may trigger ER stress. As shown in Figure 4A, incubation of HMEC-1 cells with 4-HNE (20 µmol/L) induced the phosphorylation of Ire1 and eIF2, peaking after 10 to 14 hours. Similarly, 7-ketocholesterol (10 µmol/L), another oxidized lipid that plays a role in the apoptotic effect of oxLDLs, also induced the phosphorylation of Ire1 and eIF2, (Figure 4B). These data strongly suggest that oxysterols and lipid peroxidation derivatives of polyunsaturated fatty acids participate in the activation of ER stress by oxLDLs.
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N-Acetylcysteine Prevents oxLDL-Induced ER Stress
oxLDLs and oxidized lipids are known to trigger intracellular generation of reactive oxygen species (ROS) and cellular oxidative stress29,30 that may trigger ER stress.31 This led us to investigate whether antioxidants may prevent the oxLDL-induced ER stress. Among the antioxidants tested in preliminary experiments, N-acetylcysteine (NAC) was the most effective and prevented the phosphorylation of Ire1 and eIF2 triggered by oxLDLs (Figure 5A), 7-ketocholesterol (Figure 5B), and 4-HNE (Figure 5C). These data suggest that oxidative stress triggered by oxidized lipids is involved in ER stress induction and that NAC is able to prevent it.
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ER Stress Is Involved in oxLDL-Induced Apoptosis Through JNK Activation
Prolonged ER stress is known to mediate apoptosis through CHOP induction and c-Jun N-terminal kinase (JNK) activation.19 Because oxLDLs induced a protracted and intense activation of ER stress sensors PERK and Ire1, and induced CHOP mRNA, a classic marker of ER stress-dependent apoptosis (Figures 1 and 2
), we expected the activation of JNK/stress-activated protein kinase (JNK/SAPK), which is activated through the Ire1/ASK1 pathway.32 As shown in Figure 6A, oxLDLs induced a time-dependent phosphorylation of JNK, which was completely inhibited in cells treated with siRNA specific for Ire1 (Figure 6B). Moreover, siRNA silencing of Ire1, in part, prevented the oxLDL-mediated apoptosis (Figure 6C and 6D) and DEVDase (caspase) activation (Figure 6E). The proapoptotic role of JNK in our experimental model was supported by the effect of the JNK inhibitor SP600125, which, in part, inhibited the oxLDL-mediated apoptosis (Figure 6C through 6E).
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Altogether, these data strongly suggest that ER stress plays a role in oxLDL-induced apoptosis through a pathway involving Ire1 and JNK.
ORP150 Expression Inhibits ER Stress and Apoptosis Induced by oxLDLs
ORP150 is an antiapoptotic ER-resident chaperone, induced by hypoxia and oxidative stress, that exerts a protective effect against ER stress-dependent apoptosis.23–25 We investigated whether ORP150 overexpression could protect against oxLDL-mediated apoptosis by modulating ER stress. For this purpose, we used either HMEC-1 cells stably transfected with an ORP150 cDNA-containing vector (ORP-HMECs), compared to HMEC-1 cells transfected with the empty vector (ev-HMEC), or HMEC-1 cells treated with siRNA specific for ORP150 (Figure 7A).
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ORP150-forced expression was associated with increased resistance of cells to oxLDL-induced cytotoxicity and apoptosis, whereas ORP150 silencing by siRNA potentiated oxLDL-induced cell death and DVEDase activation (Figure 7B and supplemental Figure II). The expression of XBP1, sXBP1, and CHOP mRNA were significantly attenuated in ORP-HMECs incubated with oxLDLs (Figure 7C and supplemental Figure III). Moreover, the phosphorylation of eIF2, Ire1, and JNK was inhibited in ORP-HMECs (Figure 7D and 7E), in agreement with the resistance of these cells to oxLDL-induced apoptosis.
Moreover, oxLDLs triggered the activation of Akt/PKB, a survival signaling pathway, as shown by Akt phosphorylation in wild-type HMECs and in ORP-HMECs (supplemental Figure IV, A). In contrast, oxLDL-induced Akt phosphorylation was strongly inhibited in ORP150-silenced cells (Figure IV, B). This suggests that ORP150 depletion reduces the oxLDL-induced activation of the Akt survival pathway. This mechanism may participate in the increase of oxLDL-induced apoptosis observed in ORP150-silenced HMECs (Figure 7B and supplemental Figure II).
Because ORP150 can prevent structural alteration of proteins in ER,23,24 we investigated whether ORP150, like GRP78, could bind the ER stress sensors, thereby inhibiting UPR induction. This was explored by coimmunoprecipitating ORP150 with the ER stress sensors Ire1, PERK, and ATF6 from ev-HMECs and from ORP-HMEC. As shown in Figure 8A through 8C, in ORP-HMEC, ORP150 was detected in the immunoprecipitates of each ER stress sensor (PERK, ATF6, Ire1) under basal and oxLDL-stimulated conditions. In contrast, ORP150 was not or only slightly present on ER stress sensor immunoprecipitated from ev-HMEC. These data indicate that, in cells expressing constitutively ORP150, this ER chaperone may bind the ER stress sensors. This may participate to maintain them in an inactive state (Figure 7E through 7G), thereby contributing to inhibit, limit, or delay the UPR activation by oxLDLs.
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Because ORP150 is expressed in atherosclerotic lesions in human vessels,25 we investigated whether it may interact in vivo with the nonphosphorylated form of Ire1. As shown in Figure 8D, coimmunoprecipitation experiments of Ire1 and ORP150 performed on protein extracts from carotid atherosclerotic plaque clearly indicated the interaction between both proteins in atherosclerotic lesions, whereas no or very low ORP150 was observed on Ire1 immunoprecipitates from normal human mammary artery. In contrast, the phosphorylated form of Ire1 and ORP150 did not coimmunoprecipitate in tissue extracts from normal artery and atherosclerotic lesions (Figure 8E).
Altogether, these data indicate that ORP150 overexpression inhibits or delays ER stress in vascular cells stimulated with oxLDLs by interacting with ER stress sensors and by maintaining them in an inactive state. The observation that ORP150 and Ire1 also interact in situ in atherosclerotic lesions suggests that ORP150 may contribute to protect ER function and control apoptosis in the vascular wall.
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Discussion |
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In this study, we report that ER stress is induced by oxLDLs in human vascular cells and modulate the balance between survival and apoptosis induced by oxLDLs. The detection of ER stress markers (phospho-Ire1
and KDEL motif–bearing proteins) in human stable and advanced atherosclerotic lesions exhibiting high 4-HNE adduct staining indicates that lipid oxidation products (such as 4-HNE and 4-HNE–containing LDL) probably contribute to induce ER stress within the plaque. Forced expression of the ER-resident chaperone ORP150 inhibits ER stress induction triggered by oxLDLs by interacting with the ER stress sensors in vitro and in vivo in atherosclerotic lesions, which suggests that ORP150 could modulate ER stress in the vascular wall.
The first important result of this study is the induction of ER stress by oxLDLs and its potential involvement in oxLDL-induced apoptosis. The oxLDL-induced ER stress and UPR were assessed by the phosphorylation of ER stress sensors and the expression of ER-resident chaperones.33 UPR is an adaptive response that first tends to restore ER activity and cellular homeostasis but switches toward apoptosis when ER stress is prolonged, depending on the nature of the agent and of the stress intensity.34 The most significant evidence showing the oxLDL-dependent switch of ER stress toward apoptosis was supported by the persistent expression of CHOP, a transcription factor induced through the ATF6 and PERK pathways and possibly by Ire1.35,36 CHOP induces the transcription of several proapoptotic genes such as Gadd34, ERO1, or DR537,38 and represses the transcription of the antiapoptotic factor Bcl-2.39 However, its final involvement in apoptosis is not really clarified. Thus, we also explored the role of Ire1, which can trigger ER stress–dependent apoptosis through the JNK/SAPK proapoptotic pathway,40 which is activated by oxLDLs.8,41 Here we show that JNK was activated by oxLDLs, in agreement with previous reports,8,41 and that silencing Ire1 by siRNA blocked the phosphorylation of JNK and, in part, inhibited the oxLDL-induced by apoptosis, in agreement with the role of Ire1 and JNK on cadmium-induced apoptosis.42
The cellular events leading to ER stress induction by oxLDLs include an oxidative stress, as suggested by the protective effect of the antioxidants NAC (present work) and PDTC (data not shown) and in agreement with the known role of oxidative stress in the activation of UPR, in response to oxidatively modified or misfolded protein accumulation.31 Moreover, lipid oxidation products present in oxLDLs are also involved in ER stress induction because 7-ketocholesterol or 4-HNE (used at concentrations relevant to those generated during LDL oxidation43,44) mimicked the effect of oxLDLs by triggering the phosphorylation of Ire1 and eIF2. These data are in agreement with the observation of Pedruzzi et al45 showing that 7-ketocholesterol activates the Ire1/JNK signaling pathway, CHOP mRNA expression, and apoptosis of aortic smooth muscle cells via the activation of Nox-4 and oxidative stress. Recent findings indicate that the apoptosis of macrophages elicited by free cholesterol involves the mitochondrial apoptotic pathway and results from cholesterol trafficking to ER and the induction of UPR-dependent caspase activation.46,47
4-HNE (either free or originating from oxLDLs) can modify the cellular proteins by forming adducts on free amino groups and thiol residues, thereby leading to structural alteration of proteins, inhibition of the proteasome, and accumulation of polyubiquitinated proteins.48 Altogether, these data indicate that UPR is activated by oxLDLs and lipid oxidation products and could play a role in the initiation and the progression of atherosclerotic lesion.
oxLDLs induced the expression of ER resident chaperones, BiP (GRP78), GRP94, and ORP150, a chaperone induced by hypoxia and oxidative stress. GRP78 and GRP94 are induced by ER stress and inhibit ER stress–mediated apoptosis in hypoxic cells and ischemic neurons.15,49 The expression of ORP150 in various cell types confers resistance to apoptosis induced by celecoxib, hypoxia, or glutamate23,24,50 and in diabetes, neuronal ischemia, and atherosclerosis.25,51,52 However, the mechanisms underlying the antiapoptotic effect of ORP150 and its role on ER stress modulation are not elucidated. Here, we show that the silencing of ORP150 by specific siRNA enhances the activation of DEVDase (caspase-3) and oxLDL-induced cytotoxicity, whereas forced expression of ORP150 in ORP-HMECs confers a significant resistance to oxLDL-induced DEVDase activation and apoptosis. Interestingly, ORP150 silencing resulted in an inhibition of Akt phosphorylation, which suggests that links exist between ORP150, ER stress, and the prosurvival phosphatidylinositol 3-kinase/Akt signaling pathway, in agreement with the findings of Nakatani et al53 indicating that the phosphorylation state of IRS1 and Akt is strongly altered in the liver of mice expressing an antisense form of ORP150. Because Akt downregulation induces CHOP expression and cell death,54 it can be hypothesized that enhanced apoptosis observed in HMEC-1 cells silenced for ORP150 (which results in Akt inhibition) is attributable, at least in part, to an inhibition of the phosphatidylinositol 3-kinase/Akt pathway, in agreement with our previous report.4 On the other hand, forced expression of ORP150 attenuates the activation of ER stress apoptotic pathways induced by oxLDLs, as shown by the reduced phosphorylation of Ire1 and JNK and expression of XBP1, sXBP1, and CHOP mRNAs. Besides the known properties of ORP150, centered on calcium buffering and protection against ER-calcium stores depletion,24,51 we report here that ORP150 can bind the ER stress sensors PERK, ATF6, and Ire1, which probably maintains them in an inactive state, thereby inhibiting UPR. This "binding" mechanism is known for GRP78 under basal conditions, while under stress-inducing conditions, this chaperone preferentially binds misfolded proteins, which leads to the ER stress sensors activation. It is to note that in ev-HMEC, ORP150 is poorly expressed under basal conditions and thus can neither bind the ER stress sensors nor prevent UPR. In ev-HMECs, the oxLDL-induced expression of ORP150 depends on UPR induction and occurs as a consequence of (thus after) ER stress sensors activation. In contrast, in ORP-HMECs, ORP150 is expressed before oxLDL treatment and, therefore, allows maintenance of inactive the ER sensors under basal and stress conditions. These data suggest that oxLDL-induced expression of ORP150 and other ER chaperones may lead to a feedback mechanism tending to downregulate ER stress.
Finally, the expression of ER stress markers such as phospho-Ire1 and KDEL-positive cells was observed in advanced human atherosclerotic lesions, and, to a lesser extent, in stable fibrous plaques, but not in control vessels. Interestingly, this expression was observed in atherosclerotic areas containing high level of 4-HNE adducts, thus suggesting that lipid peroxidation derivatives present in advanced atherosclerotic lesions (as previously reported by Jurgens et al55 for 4-HNE and by Myoishi et al10 for oxysterols) may locally contribute to trigger ER stress. Another finding of this work is the interaction between ORP150 and the inactive nonphosphorylated Ire1 in the vascular wall, as evidenced by coimmunoprecipitation experiments, in agreement with the results reported for BiP (GRP78) by Bertolotti et al18 showing that the interactions between BiP and PERK, or Ire1, implicate the nonphosphorylated form of the sensors.
The role of ER chaperones in atherosclerosis is still unclear. In a recent review, Ni and Lee56 report the beneficial properties of GRP78 overexpression, which could slow down the progression of atherosclerosis through several mechanisms including (1) modulation of ER stress (mediated by homocysteine); (2) inhibition of vascular cell apoptosis; (3) inhibition of tissue factor procoagulant activity; and (4) inhibition of sterol regulatory element binding protein activation; sterol regulatory element binding proteins are involved in the activation of genes of the cholesterol and triglyceride biosynthesis pathways. Interestingly mice overexpressing ORP150 exhibit severe growth retardation and vacuolar muscle degeneration but also low serum concentration of triglycerides, cholesterol, and insulin, as well as increased glucose catabolism,57 in agreement with Nakatani et al,53 who report a beneficial role of ORP150 on insulin resistance and glucose tolerance.
These reports, as well as our data on the increased expression of ORP150 in advanced carotid lesions, suggest a protective role for ORP150 against ER stress, deregulation of calcium homeostasis,27 and apoptosis, and thereby support speculation that ORP150 expression could be beneficial under the local challenging conditions of severe atherosclerosis. In contrast, ORP150 downregulation could aggravate vascular apoptosis, thereby increasing the risk of plaque rupture, thrombosis, and cardiovascular events.
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Acknowledgments |
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Dr Virginie Gallet (Société Nationale des Chemins de Fer Laboratory, Toulouse, France) is gratefully acknowledged for providing human sera. We thank Elodie Mucher, Marie-Hélène Grazide, and Corinne Bernis for excellent technical assistance.
Sources of Funding
This work was supported by Institut National de la Santé et de la Recherche Médicale, L’Agence Nationale de Recherches (LiSA project no. ANR-05-PCOD-019-01); Université Paul Sabatier, Fondation Coeur et Artères (FCA-06T6); Fondation pour la Recherche Médicale (DCV2007040927); and European COST-B35. M.S. is the recipient of a Groupe de Réflexion sur la Recherche Cardiovasculaire grant.
Disclosures
None.
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Footnotes |
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Original received July 23, 2008; revision received December 11, 2008; accepted December 11, 2008.
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