Published online before print April 7, 2005, doi: 10.1161/01.ATV.0000164805.73558.80
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
High-Density Lipoproteins Prevent the Oxidized Low-Density Lipoprotein–Induced Endothelial Growth Factor Receptor Activation and Subsequent Matrix Metalloproteinase-2 Upregulation
From INSERM U-466 and Biochimie IFR-31 (F.R., N.A., C.V., A.-V.C., A.N.-S., R.S.), Faculty of Medicine, University Paul Sabatier, Toulouse, France; INSERM U-563 (R.B.), Centre de Physiopathologie de Toulouse-Purpan, Department Lipoproteines et Mediateurs Lipidiques, IFR-30, Toulouse, France.
Correspondence to R. Salvayre or A. Negre-Salvayre, Biochimie, INSERM U466, IFR-31, CHU Rangueil, 1, avenue Jean Poulhès, TSA-50032, 31059 Toulouse Cedex 9, France. E-mail salvayre{at}toulouse.inserm.fr or anesalv@toulouse.inserm.fr
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Abstract |
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Objectives— The atherogenic oxidized low-density lipoprotein (oxLDL) induces the formation of carbonyl-protein adducts and activates the endothelial growth factor receptor (EGFR) signaling pathway, which is now regarded as a central element for signal transduction. We aimed to investigate whether and by which mechanism the anti-atherogenic high-density lipoprotein (HDL) prevents these effects of oxLDL.
Methods and Results— In vascular cultured cells, HDL and apolipoprotein A-I inhibit oxLDL-induced EGFR activation and subsequent signaling by acting through 2 separate mechanisms. First, HDL, like the aldehyde scavenger dinitrophenyl hydrazine, prevented the formation of oxLDL-induced carbonyl–protein adducts and 4-hydroxynonenal (HNE)–EGFR adducts. Secondly, HDL enhanced the cellular antioxidant defenses by preventing (through a scavenger receptor class B-1 (SR-BI)–dependent mechanism) the increase of intracellular reactive oxygen species (ROS) and subsequent EGFR activation triggered by oxLDL or H2O2. A pharmacological approach suggests that this protective effect of HDL is independent of cellular glutathione level and glutathione peroxidase activity, but it requires catalase activity. Finally, we report that oxLDL upregulates both membrane type 1 (MT1)-matrix metalloproteinase-1 (MT1-MMP) and MMP-2 through an EGFR-dependent mechanism and that HDL inhibits these events.
Conclusions— HDLs block in vitro oxLDL-induced EGFR signaling and subsequent MMP-2 activation by inhibiting carbonyl adducts formation and cellular oxidative stress. These effects of HDL may participate to reduce cell activation, excessive remodeling, and alteration of the vascular wall.
Oxidized LDLs induce EGFR activation and subsequent MMP-2 activation. HDLs inhibit these events by 2 separate mechanisms, ie, by blocking carbonyl–protein adduct formation and by inhibiting the oxLDL-induced and H2O2-induced intracellular ROS increase, through a catalase-dependent process. This may contribute to reduce cell activation, excessive remodeling, and vascular wall alteration.
Key Words: atherosclerosis • endothelial growth factors • lipoproteins
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Introduction |
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Low-density lipoproteins (LDLs) are thought to become atherogenic after undergoing oxidative modifications.1–3 Oxidized LDLs (oxLDLs) trigger cell signaling pathways involved in cellular responses, such as proliferation, inflammation, and apoptosis, which occur during atherogenesis.4–7 In contrast, high-density lipoproteins (HDLs) are anti-atherogenic and cardioprotective.8 Besides their role in the reverse transport of cholesterol, 9 HDL inhibits LDL oxidation and cell signaling mediated by oxLDL, and counters several adverse biological effects, such as cytotoxicity and inflammatory response triggered by cytokines, oxLDL, or oxidants.4,10–12 The molecular mechanism of this protective effect of HDL is only partly understood.
The endothelial growth factor receptor (EGFR) family consists of 4 members of tyrosine kinase receptors, EGFR (or ErbB1), HER2 (or ErbB2/neu), HER3 (or ErbB3), and ErbB4. EGFR is activated by binding of specific peptide ligands (EGF, transforming growth factor-
, amphiregulin, neu differentiation factor [NDF], neuregulins, heregulins, heparin-binding epidermal growth factor [HB-EGF], betacellulin, and epiregulin);13–15 nonspecific and/or stress stimuli, such as ultraviolet and gamma radiations, alkylating agents signaling,16,17 oxidized lipids,18 fatty acids,19 and oxidants;20 and transactivation by several signaling pathways.21,22 For instance, cross-talk between G-protein–coupled receptor (for instance, angiotensin receptor-1 in vascular cells) and EGFR is mediated by cell signaling involving G-proteins, calcium, protein kinase C, Src, and metalloproteinases (such as a disintegrin and metalloprotease [ADAM]) that cleave pro-EGFR ligands, thereby liberating agonists of EGFR.21,22 Through these mechanisms, EGFR is a start point of a classical tyrosine kinase receptor signaling cascade, as well as a switch point of a wide cellular communication network.21,22 Therefore, EGFR acts as "a central element for signal transduction" and regulation of several cellular functions, such as cell growth, differentiation, motility, survival, and death,21 which also play a pivotal role in various pathophysiological processes. In addition to its prominent role in the development of several cancers,21 EGFR has been recently implicated in vascular pathophysiological processes associated with excessive remodeling and atherosclerosis.22,23 Among various biological effects, EGFR could play a role in cell migration,20–22 mitogenic signaling,23 and NF-
B activation,24,25 and induces the upregulation of metalloproteinases (MMPs).26
MMPs are zinc proteases that are expressed in atherosclerotic plaques, where they may contribute to vascular remodeling and plaque disruption.27–29 MMPs are regulated through gene expression and activation of latent MMPs by cleavage of the N-terminal prosegment.30 oxLDL and inflammatory cytokines enhance the expression and activity of several MMPs, such as MMP-1, MMP-9 (gelatinase B), and membrane type 1 (MT1)-MMP (that cleaves and activates MMP-2) in vascular cells.27,31,32
The reported data show that HDLs are able to modulate the oxLDL-induced EGFR activation and subsequent upregulation of MMP-2 in vascular smooth muscle cells (SMCs).
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Methods |
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A detailed Methods section is reported as an online-only data supplement (available at http://atvb.ahajournals.org).
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Results |
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HDL Inhibits oxLDL-Induced EGFR Activation
Incubation of cells with oxLDL induced mild tyrosine-phosphorylation of EGFR that was inhibited by HDL (Figure 1A and 1B). Because similar data were obtained on vascular SMCs and endothelial cell vein (ECV)-304, we used, alternatively, ECV-304 cells when high EGFR level was required. Native LDL triggered no (or only minor) EGFR activation (Figure 1A). Under the used conditions, EGFR activation began at relatively low concentrations of oxLDL (25 to 50 µg apolipoprotein B/mL), was dose-dependent, and was completely inhibited by HDL in a dose-dependent manner (Figure 1B). Of note, 200 µg apolipoprotein B/mL (UV+Cu) oxLDL were not toxic over the 5 hours of the experiments (apoptosis becoming manifest only after 12-hour incubation). oxLDL-induced EGFR activation was independent of the apoptotic effect because it occurred at low, nontoxic, concentrations of (UV+Cu) oxLDL (25 to 50 µg apolipoprotein B/mL; UV) oxLDL (which are less toxic than [UV+Cu] oxLDL) induced also EGFR activation (data not shown).
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Because 2 phases of oxLDL-induced EGFR activation can be discriminated by their antioxidant susceptibility,19 we investigated whether HDL were effective on each component. Preincubation of cells with HDL prevented the early (1-hour) and late (5-hour) phases of oxLDL-induced EGFR activation (Figure 1C) and the subsequent signaling (Figure 1D).
The Protective Effect of HDL Is Mediated by Apolipoprotein A-I and SR-B1
The oxLDL-induced EGFR activation was inhibited by delipidated HDL apolipoprotein fraction and by apolipoprotein A-I (Figure 2A). Serum albumin, which is a frequent contaminant of HDL fractions (10% to 25% of total HDL-associated proteins) but is only minor in LDL fractions (<1% of apolipoprotein B content), did not prevent oxLDL-induced EGFR activation. The inhibitory effect of HDL was lost when apolipoprotein A-I was altered by HClO-mediated oxidation (containing 3.8±0.4 nmol thiobarbituric reactive substances [TBARS]/µg apolipoprotein A). In contrast, UV-oxidized HDL (2.7±0.3 nmol TBARS/µg apolipoprotein A) that exhibited only moderately altered apolipoprotein A-I were effective to prevent oxLDL-induced EGFR activation (Figure 2B). The protective effect of HDL was abolished by co-incubation of cells with HDL and anti-SRB1 antibodies (Figure 2C). This suggests that this effect of HDL requires the interaction between HDL and SRB1. Finally, paraoxonases were not implicated in this protective effect, because HDL fractions with very low paraoxonase activity (prepared in the presence of EDTA 100 µmol/L) and HDL fractions with high paraoxonase activity (prepared without EDTA) exhibited the same inhibitory effect (Figure 2D). These data strongly suggest that the protective effect of HDL against oxLDL-induced EGFR activation is mainly mediated through the interaction of apolipoprotein A-I with SRB1.
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HDL Prevent the Formation of oxLDL-Induced Carbonyl–Protein Adducts and HNE–EGFR Adducts
oxLDL-induced EGFR activation results from HNE–EGFR adduct formation and reactive oxygen species (ROS) generation.18,19 This led to examining whether HDL may prevent the formation of HNE-EGFR adducts and other oxidized lipid–protein adducts. As shown in Figure 3A, HNE–EGFR adducts and EGFR activation induced by oxLDL were inhibited by HDL. More generally, HDL prevented the oxLDL-induced formation of carbonyl–protein adducts and the loss of [3H]NSP-reactive amino groups of cell proteins induced by oxLDL (Figure 3B and 3C). This effect was partly mimicked by the aldehyde scavenger dinitrophenyl hydrazine that prevented completely the formation of oxLDL-induced HNE–EGFR adducts and inhibited in part the oxLDL-induced EGFR activation (Figure 3A, right panel). Interestingly, Trolox, a hydrosoluble analog of tocopherol, induced a strong inhibition of EGFR autophosphorylation, but reduced only partly the level of HNE–EGFR adducts (Figure 3A). These data suggest that HDL are able to inhibit the oxLDL-induced EGFR activation (dinitrophenyl hydrazine-sensitive) mediated by HNE, and led us to hypothesize that HDL could also inhibit a second mechanism (Trolox-sensitive) involved in oxLDL-induced EGFR activation.
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HDL Inhibits oxLDL-Induced ROS Increase and Subsequent EGFR Activation
Because HDL inhibit an early increase of oxLDL-induced cellular ROS,33 and because ROS reinforce EGFR activation,16 we investigated whether HDL blocked the oxLDL-induced EGFR activation through a ROS-dependent mechanism. As reported in Figure 4, the oxLDL-induced cellular ROS increase (monitored by the fluorescence of oxidized dihydrorhodamine 123 [DHR] probe) was inhibited by HDL (Figure 4A) in a dose-dependent manner (Figure 4B). This inhibitory (protective) effect was lost with HClO-oxidized HDL, but not with UV-oxidized HDL (Figure 4C). Because apolipoprotein A-I is degraded in HClO-oxidized HDL, but is less altered in UV-oxidized HDL, it is suggested that this inhibitory effect of HDL requires the integrity of apolipoprotein A-I. Interestingly, preincubation of cells with anti-SRB1 antibody abrogated the protective effect of HDL (Figure 4C), thus suggesting that this effect is mediated through HDL/SRB1 interaction. Because EGFR activation by ROS and oxLDL results in part from the inactivation of phosphotyrosine phosphatases (PTPases),17,19,34 we examined whether HDLs were able to prevent the oxLDL-induced inhibition of PTPases. Under preincubation and coincubation conditions, HDL prevented effectively the oxLDL-induced inhibition of PTPases (Figure 4D). This protection of PTPases explains, at least in part, the protective effect of HDL against the oxLDL-induced EGFR activation. Interestingly, under "preincubation only" experimental conditions (cells were preincubated with HDL for 18 hours, then HDLs were removed just before oxLDL addition), HDLs were also able to block the oxLDL-induced ROS increase (Figure 4A) and EGFR activation (Figure 4E). Because, under "preincubation only" conditions, HDL were not in contact with oxLDL, we hypothesized that the persisting effect of HDL could result from HDL–cell contact, which may modulate intracellular ROS production or degradation.
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HDLs Prevent the oxLDL-Induced H2O2 Increase Through a Catalase-Dependent Mechanism
As shown in Figure I (available online at http://atvb.ahajournals.org), HDL prevented both the intracellular ROS increase (Figure IA) and EGFR activation triggered by exogenous H2O2 (Figure IB), thus suggesting that HDLs stimulate the cellular degradation of H2O2. The degradation of oxLDL-induced ROS stimulated by HDLs was (partly) blocked by aminotriazole (a catalase inhibitor), but not by buthionine sulfoximine (a glutathione-depleting agent), and by mercaptosuccinate (a glutathione peroxidase inhibitor; Figure IC and ID). This suggests that HDL-induced ROS degradation is mediated by catalase. Subsequently, inhibition of oxLDL-induced EGFR activation by HDL was also catalase-dependent, but independent of glutathione and glutathione peroxidase (Figure IE). These data suggest that oxLDL-induced EGFR activation is mediated in part by H2O2 and that its inhibition by HDL is partly dependent on catalase activity.
oxLDLs Induce the EGFR-Mediated Upregulation of MMP-2 Inhibition by HDLs
MMPs play a critical role in extracellular matrix degradation, tissue remodeling, aneurysm formation, and plaque rupture.27–30 MMP-2 is implicated in SMC mitogenic signaling35 and intimal hyperplasia.36 The expression of MMPs is regulated by pro-inflammatory molecules and oxidized lipids.27,31,32 Moreover, EGFR is involved in the regulation of MMPs expression.26 Because MT1–MMP, which activates MMP-2 (gelatinase A), is expressed in atherosclerotic lesions and is upregulated by oxLDL,32 we investigated whether MMP-2 was also regulated and activated by oxLDL, and whether HDLs were able to prevent the increase of MT1–MMP and MMP-2. oxLDL (100 µg apolipoprotein B/mL) stimulated MMP-2 expression at 16 hours and MMP-9 expression at 36 hours (Figure 5A). We also observed the processing of pro-MT1–MMP in its active form, MT1–MMP (Figure 5B), in agreement with Rajavashisth et al.32 The upregulation of MMP-2 expression at 16 hours was associated with an increase of the activity of MMP released in the culture medium (Figure 5C). Pro–MMP-2 upregulation, MT1–MMP activation, and subsequent release of active MMP-2 were strongly inhibited by HDL and by AG-1478, a specific inhibitor of EGFR (Figure 5A to 5C). In contrast, the upregulation of pro–MMP-9 expression was only partly inhibited by HDL (Figure 5A and 5B) and was poorly inhibited by AG-1478. This suggests a role for EGFR in the activation of MT1–MMP and MMP-2. Altogether, these results indicate that the activation of SMCs by oxLDL enhances the expression of MMP-2 and the release of active MMP-2 through an EGFR-dependent mechanism, and that HDLs are effective in blocking these events.
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Discussion |
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The major finding of the present study is that in vascular SMCs, HDLs are able to prevent HNE–protein adduct formation, oxidative stress, oxLDL-induced EGFR activation, and the subsequent upregulation and activation of MMP-2 (Figure II, available online only at http://atvb.ahajournals.org). oxLDL and oxidants are able to trigger a moderate and sustained activation of EGFR15–19,22 through (at least) 2 mechanisms, 4-HNE–EGFR adduct formation and intracellular ROS generation.18,19 EGFR is now considered as a convergence point in the complex signaling network that regulates cellular functions (such as cell growth, differentiation, motility, survival/death) and thereby plays a pivotal role in various pathophysiological processes.13–15 Besides its obvious role in cancer progression or metastasis,21 the role of EGFR in vascular biology, angiogenesis, and atherosclerosis is being recognized.3,20,23
Our data show, for the first time to our knowledge, that HDLs can prevent oxLDL-induced EGFR activation by inhibiting both the 4-HNE–EGFR adduct formation and the ROS-dependent mechanism (PTPase inactivation) involved in the sustained oxLDL-induced activation of EGFR. HDLs prevent HNE–protein adduct formation by acting probably through 2 mechanisms. First, HDLs are able to react with HNE37,38 and act like the aldehyde scavenger dinitrophenyl hydrazine (Figure 3). But, this "scavenger" activity of HDL required the presence of cells, because HDLs coincubated with oxLDL in cell-free medium did not scavenge the oxLDL-associated HNE (data not shown) and because the transfer of HNE from oxLDL to cell proteins is blocked in part by metabolic inhibitors.39 Moreover, HDLs, by acting through an antioxidant mechanism,33 inhibit the oxidative stress induced by oxLDL or H2O2 (Figures 4 and 5 
), thereby reducing the formation of peroxidation derivatives of cellular lipids and, subsequently, of aldehyde–protein adducts. Because lipid peroxidation derivatives are present in atherosclerotic lesions and are thought to play a role in atherogenesis,39,40–42 the inhibitory effect on the aldehyde–protein adduct formation might explain in part their anti-atherogenic effect. In our experimental model system, paraoxonase activity is not required for this "scavenger" activity of HDL, because HDL preparations with high or low paraoxonase activity and apolipoprotein A-I fraction with no detectable paraoxonase activity exhibited similar protective properties. Of course, our observation does not exclude that paraoxonases may act in vivo by other mechanisms.10
A second mechanism of action of HDL results from the inhibition of the increase of oxLDL-induced cellular ROS. This may result either from the inhibition of ROS biosynthesis or from increased ROS degradation. The latter hypothesis is supported by the fact that HDLs enhance H2O2 catabolism in cells incubated with exogenous H2O2. Moreover, this HDL-induced H2O2 degradation requires a cellular process, because in "preincubation only" experiments, HDL increase the resistance of cells against exogenous oxidative stress and because HDLs induce no significant H2O2 degradation in cell-free medium. This protective effect of HDL did not require glutathione and glutathione peroxidase activity, but was partly dependent on catalase activity, because the catalase inhibitor aminotriazole abrogated in part the protective effect of HDL. To date, the molecular mechanism by which HDL promotes the catalase-mediated H2O2 degradation remains unknown (under the used conditions, HDL did not induce any upregulation of the total cellular catalase activity; data not shown).
oxLDL and MMP are colocalized in atherosclerotic plaques and are thought to play a crucial role in vascular remodeling, pathogenesis of atherosclerosis, and plaque instability.27–29 Because several MMPs are upregulated by oxLDL in vascular cells,27,31,32 and by H2O243,44 or EGFR activation45 in cancer cells, this led us to investigate whether MMP upregulation was mediated through EGFR transactivation and whether HDLs were able to counter this MMP upregulation. oxLDL (16-hour incubation) induced the expression of MMP-2, whereas, at this time, MMP-9 was only poorly expressed. Interestingly, at the same time, we observed, in agreement with Rajavashisth,32 an increase of the active (processed) form of MT1–MMP, which cleaves and activates MMP-2. oxLDL-induced expression and activation of MT1–MMP and MMP-2 were coordinately regulated through EGFR transactivation, in agreement with Menashi et al.26 Both the oxLDL-induced expression and activation of MT1–MMP and MMP-2 were strongly inhibited by HDL (Figure II). In contrast, the regulation of the oxLDL-induced expression of MMP-9 (peaking at 36 hours) was not dependent on EGFR signaling and was only partly inhibited by HDL. From a pathophysiological point of view, this could be of importance in the pathogenesis of atherosclerosis, because MMPs are overexpressed in atherosclerotic lesions and could act in the atherosclerosis process.27,29 Active MMP-2 may degrade basement membrane collagen type IV and may favor the local desquamation of endothelial cells by lysing contacts with the underlying extracellular matrix, thereby participating in plaque erosion.27 Moreover, MMP-2 (with MMP-9 and urokinase plasminogen activator) may also participate in the excessive proteolysis of extracellular matrix and outward remodeling occurring in aneurysm.27 Finally, besides its role in extracellular matrix degradation, MMP-2 activation is implicated in SMC migration and proliferation, as shown in experimental neointimal hyperplasia36 and in oxLDL-induced proliferation mediated by the sphingomyelin/ceramide/sphingosine-1 phosphate pathway.35
The inhibitory effect of HDLs described here acts in concert with other protective effects. For instance, the same concentration of HDLs prevents the toxic effect of oxLDL.46 However, oxLDL-induced EGFR activation and toxicity are not causally related because EGFR activation was triggered by low nontoxic, as well as at high toxic, concentrations of oxLDL, and because both events are dissociated by inhibitors.47 All these protective effects of HDL may converge to inhibit "inflammatory" cell signaling triggered by oxLDL and, finally, to protect the integrity of the arterial wall. It is not excluded that the reported results, obtained under in vitro experimental conditions, may also play a role in atherogenesis, because accompanying events, such as 4-HNE–protein adduct formation,8,39 and MMP activation occur in atherosclerotic areas,27–29 and because HDLs are able to slow atherosclerotic lesion formation.4,11,12 However, the role of oxLDL-induced EGFR activation and subsequent MMP-2 activation in the atherogenic process remain to be evaluated in vivo.
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Acknowledgments |
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This work was supported by grants from INSERM and University Paul Sabatier. The authors thank C. Mora and B. Bocquet for the technical assistance. F. Robbesyn was recipient of a fellowship from "Fondation pour la Recherche Médicale."
Received September 13, 2004; accepted March 18, 2005.
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