Current Medicinal Chemistry, 2008, 15, 3011-3024
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PPAR and Early Human Placental Development Thierry Fournier*,1,5, Patrice Thérond3,4, Karen Handschuh1,5, Vassilis Tsatsaris1,2,5 and Danièle Evain-Brion1,5 1
INSERM, U767, Paris, F-75006, France; Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, F-75006 Paris, France; 2AP-HP, Hôpital Cochin, Maternité Port-Royal, 75014 Paris, France; 3Université Paris Descartes, EA3617, Département de Biochimie, Faculté de Pharmacie, 75006 Paris, France; 4CH de Versailles, 78157 Le Chesnay, France; 5PremUP, Foundation, 75006 Paris, France Abstract: During pregnancy, the placenta ensures multiple functions, which are directly involved in the initiation, outcome of gestation and fetal growth. Human implantation involves a major invasion of the uterus wall and a complete remodeling of the uterine arteries by the extravillous cytotrophoblasts (EVCT) during the first trimester of pregnancy. Abnormality of these early steps of placental development leads to poor placentation, fetal growth defects and is very often associated with preeclampsia, a major and frequent complication of human pregnancy. Unexpectedly, genetic studies performed in mice established that the peroxisome proliferator-activated receptor- (PPAR) is essential for placental development. In the human placenta, PPAR is specifically expressed in the villous cytotrophoblast (VCT) and the syncytiotrophoblast (ST) as well as in the EVCT along their invasive pathway. To study the mechanisms that control human trophoblast invasion during early placental development and to provide new insight in the understanding of preeclampsia, we have developed in vitro models of human invasive trophoblasts. We observed that activation of the ligand-activated nuclear receptor PPAR agonists inhibits the trophoblastic invasion process in a concentration-dependent manner. Analysis of PPAR-target genes revealed that placental growth hormone, the protease PAPP-A and the human chorionic gonadotropin hormone (hCG) might be involved in the PPAR-mediated effect in an autocrine manner. The presence of oxidized-LDLs at the maternofetal interface suggests that oxidized-LDLs from maternal sera might be a source of potential PPAR ligands for the trophoblasts. Indeed, oxidized-LDLs decrease trophoblast invasion in vitro and analysis of their content revealed that they contain potent PPAR agonists such as eicosanoids, but also oxysterols, which are ligands for another nuclear receptor, the liver X Receptor (LXR). LXRß was found to be expressed in trophoblast and LXR agonists shown to inhibit trophoblast invasion. Together, these data underscore a major role for PPAR in the control of human trophoblast invasion during early placental development and suggest that ligands such as oxidized-LDLs at the implantation site might contribute to the modulation of trophoblast invasion through activation of PPAR and LXRß, two nuclear receptors that modulate the human trophoblastic cell invasion process.
Keywords: Trophoblast invasion, nuclear receptors, PPAR, LXR, ligands, oxidized LDL, preeclampsia. DEVELOPMENT OF HUMAN PLACENTA During pregnancy, the placenta ensures multiple functions (maternofetal exchanges, hormonal functions and immunomodulation), which are directly involved in the initiation and outcome of gestation, fetal growth, and possibly the initiation of parturition. Numerous pregnancy abnormalities are related to placental dysfunctions and utero-placental interface dysfunctions. Human placentation has numerous particularities and is characterized by major trophoblastic invasion allowing a direct contact of trophoblast with maternal blood, and by the intensity and specificity of its hormonal functions. The structural and functional unit of the placenta is the chorionic villous, Fig. (1A). After the initial phase of implantation the trophoblast differentiates along two distinct pathways: the villous (VCT) and extravillous (EVCT) cytotrophoblasts. These two trophoblast subtypes display different phenotypes and functions. The mononucleated VCT that cover the floating chorionic villi aggregate and fuse to form the syncytiotrophoblast which is the site of exchanges in gases and nutrients between the maternal and the fetal blood. The ST also represents the endocrine tissue of human placenta by secreting in maternal blood essential hormones for the maintenance of pregnancy such as human chorionic *Address correspondence to this author at the INSERM, U767, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l’Observatoire, 75006 Paris, France; Tel: +33 1 53 73 96 03; Fax: +33 1 44 07 39 92; E-mail:
[email protected] 0929-8673/08 $55.00+.00
gonadotropin (hCG), progesterone, leptine, placental growth hormone etc. Thus, anomalies in ST formation or function may interfere with main functions of placenta and directly alter fetal growth. The cytotrophoblasts located at the tip of the anchoring villi contacting the uterine wall follow a different differentiation pathway and undergo a complex process of proliferation, migration and invasion. These cells, (EVCT), proliferate to form multilayered columns of cells and then invade the decidua up to the upper third of the myometrium. EVCT also specifically invade the uterine arterioles through endovascular or perivascular routes, and replace the endothelial lining and most of the musculoelastic tissue of the vessel wall leading to low resistance vessels. Hence, EVCT are directly involved in the anchoring of chorionic villi in the uterus, and in the remodeling of the uterine arterioles. This invasion process and remodeling of the utero-placental vasculature are essential to provide adequate supply of maternal blood into the intervillous space necessary for fetal growth [1-5]. This invasion process is illustrated on Fig. (1B) showing a first trimester placental tissue section immunostained for cytokeratin 7 (CK7), a specific marker for cytotrophoblasts. EXPRESSION AND ROLE OF PPAR IN PLACENTAL DEVELOPMENT The peroxisome proliferator-activated receptor- (PPAR) is a member of the nuclear receptor superfamily that controls the expression of a large array of genes in a © 2008 Bentham Science Publishers Ltd.
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Fig. (1). A) Scheme of chorionic villi at the maternofetal interface. B) Immunohistochemistry of a placental tissue section at the implantation site showing specific trophoblast labeling with anti-cytokeratin 7 (CK7) antibody. VCT: villous cytotrophoblast; ST: syncytiotrophoblast; EVCT: extravillous cytotrophoblast.
ligand-dependent manner. DNA binding of PPAR to its response element (composed of a direct repeat of the core hexanucleotide motif AGGTCA with one intervening base named DR1) requires heterodimerization with another nuclear receptor, the retinoid X receptor (RXR); for review see [6]. PPAR is bound and activated by natural ligands such as eicosanoids, fatty acids [7] and oxidized low-density lipoprotein compounds [8]. 15-deoxy-delta (12,14) prostaglandin J2 (15d-PGJ2) is also considered as a potent natural PPAR agonist [9, 10]. In addition, synthetic agonists of PPAR, such as rosiglitazone that belongs to the thiazolidinedione class of drugs, have been developed and used in the treatment of type 2 diabetes. PPAR/RXR heterodimers can be activated by either selective RXR (9-cis retinoic acid) or PPAR ligands, the combination resulting in an additive or synergistic effect. In 1999, genetic studies performed in mice established that two nuclear hormone receptors, RXRs, on the one hand, and PPAR, on the other hand, are essential for placental development and vasculature. Indeed, RXR-/- /RXR-/conceptuses fail to develop a normal chorioallantoic placenta with a functional labyrinthine zone, resulting in compromised maternal-fetal exchanges and therefore in early embryonic death [11]. Likewise, PPAR-/- conceptuses exhibited similar placental dysgenesis with defects in trophoblast differentiation and vascular processes [12, 13]. These studies demonstrated that PPAR/RXR heterodimers are essential for implantation and the formation of a functional placenta in mice. In human placenta, PPAR is specifically expressed in the VCT and the ST during first trimester of pregnancy and
at term and, as well as in the EVCT along their differentiation pathway, including proliferative and intermediate EVCT in the proximal and distal columns of the anchoring villi, invasive EVCT located in the deciduas, endovascular and perivascular EVCT, and giant cells; for review see [14]. Therefore, PPAR may represent a specific marker of human trophoblast. By contrast, a pleiotropic expression of the isoform alpha of RXR was found at the maternofetal interface, RXR being expressed in trophoblast from villous and extravillous origin, the mesenchymal core of the villi and the different components of the deciduas [15, 16]. Thus, these histological studies demonstrated that at the maternofetal interface, PPAR/RXR heterodimers are exclusively located in the trophoblasts. The role of PPAR was shown in human placental development in both the villous and the extravillous cytotrophoblast differentiation pathways. Indeed, the PPAR agonist troglitazone enhances VCT differentiation into ST [17] and PPAR-induced villous trophoblast differentiation is associated with increase in hCG expression and secretion [18], an hormone that has a major role in human pregnancy and in formation of the ST in an autocrine manner. As described in other cellular models, PPAR and panRXR agonists have additive effects on the secretion of major hormones produced by the ST such as hCG, human placental lactogen (hPL), human placental growth hormone (hPGH) and leptin. Using the same in vitro model of villous trophoblast differentiation, activation of PPAR and of PPARß/ with specific agonists have no effect on hCG secretion [18], suggesting a specific role for the PPAR isoform in human VCT differentiation. As described in adipocytes, PPAR activation in primary cultures of term VCT is associated with an accumulation of neutral
PPAR and Early Human Placental Development
lipids, as assayed by oil red O staining [18]. This was also demonstrated in the EVCT invasive cell line HIPEC65 [19]. In this connection, it was recently showed that fatty acid uptake by trophoblast [20] was regulated by PPAR and its heterodimeric nuclear receptor partner RXR as described in other PPAR target cells [21, 22]. This is associated with an enhanced expression of adipophilin, a fat droplet associated protein, regulated by PPAR [23] and fatty acid (FA) transport protein FATP4 [20]. Membrane proteins such as free fatty acid transporter (FAT/CD36), fatty acid transfer protein (FATP) and plasma membrane fatty acid binding protein (FABP) and intracellular proteins (cytosolic FABP) are involved in translocation and free FA uptake into the cells. Cytosolic FABP are expressed in trophoblast cells in culture and non specific PPAR ligands do not modify linoleic acid transfer in these cells [24]. During pregnancy, placental transfer of fatty acid from the mother to the fetus is crucial for adequate fetal growth and development. It is conceivable that in the ST it is regulated by complex mechanisms evolving along pregnancy, which might involve different PPAR isoforms and a balance between PPAR-induced lipid storage and PPAR-induced lipid utilization as depicted in adipocytes. The role of PPAR in the human EVCT was essentially investigated in the regulation of the invasion process. ROLE OF PPAR IN HUMAN TROPHOBLAST INVASION The human EVCT is a unique model of a cell invasion process, sharing mechanisms with metastasis. However, in contrast to tumoral invasion, trophoblast invasion is spatially controlled and oriented: it is temporally restricted to early pregnancy and spatially confined to the endometrium, the upper third of the myometrium, and the associated spiral arterioles [5, 25]. Trophoblast migration and invasive capacity were shown to be modulated by numerous factors including oxygen concentration [26], transforming growth factor (TGF-ß), insulin-like growth factor II (IGF-II) and insulinlike growth factor binding protein 1 (IGFBP-1) [27, 28], epidermal growth factor [29] and hepatocyte growth factor [30]. Owing to the specificity of the human placenta, no readily accessible animal models are available for studying trophoblast invasion. We have thus established two in vitro models, namely cultures of primary EVCT isolated from first-trimester chorionic villi [16, 31] and a cell line obtained by transformation of these primary cells by Simian Virus 40 large T antigen [19] Fig. (2A). The first model consists of primary cultures of trophoblastic cells isolated by gentle enzymatic digestion from first trimester chorionic villi and purified as previously described [16, 31]. Cultured on an extra cellular matrix such as Matrigel, these cells are non proliferative and express specific markers of invasive EVCT such as cytokeratin 7 (CK7), human leukocyte antigen-G (HLA-G), hPL, the protooncogene c-erbB2, CD9 and the alpha5 subunit of the alpha5-beta1 fibronectin receptor [16, 19, 31]. The second model of human invasive trophoblasts was obtained from a primary culture of EVCT transformed with the simian virus 40 large T antigen. This trophoblastic cell line (HIPEC65) is proliferative and highly invasive when cultured on Matrigel and have been fully characterized [19]. HIPEC 65 cells express the CK7, HLA- G and CD9, the three essential antigens considered as EVCT specific
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markers as established in two workshop reports [32, 33]. In addition, markers of invasive trophoblasts including c-erbB2, TGFß2 and alpha5 subunit are also expressed by HIPEC65 [19]. These two in vitro models of human invasive trophoblast allowed to show that both EVCT primary cultures and HIPEC65 cells express high levels of PPAR and RXR that colocalized in the nuclei as demonstrated by immunocytochemistry [16, 19]. Activation of PPAR/RXR heterodimers by either natural (15d-PGJ2) or synthetic (rosiglitazone) PPAR ligands markedly decreased in EVCT and HIPEC65 the cell invasion process in a concentration-dependent manner as assayed in Boyden chambers as illustrated in Fig. (2B) [16, 19]. Interestingly, whereas in numerous cellular models PPAR activation inhibits both cell proliferation and migration [34, 35], it did not modify cell growth in HIPEC65 cells suggesting that inhibition of cellular invasiveness by PPAR agonists without alteration of cell growth might be specific to trophoblastic cells [19]. Cellular invasion requires different steps such as lost of cell-cell adhesion and communication, modification of receptors to the matrix such as integrins, protease activation promoting matrix degradation, cytoskeleton activation and secretion of soluble factors promoting cell migration. In order to investigate the mechanisms by which PPAR regulated the trophoblastic invasion process we analyzed gene expression of some factors known to modulate human trophoblast invasion. Thus, we observed that activation of PPAR by the specific agonist rosiglitazone significantly down regulated gene expressions of the human placental growth hormone (hPGH), the pregnancy-associated plasma protein A (PAPP-A) [36] and more recently the human chorionic gonadotropin hormone (hCG) [37]. Hormones belonging to the GH/prolactin family are expressed at the maternofetal interface and are involved in cell motility in various models. We demonstrated that invasive EVCT expressed both hPGH and human GH receptor (hGHR) and that incubation of EVCT with exogenous hPGH stimulated trophoblast invasiveness through activation of the Janus kinase-2/signal transducer and activator of transcription factor-5 (JAK2/STAT5) signaling pathway [38]. Thus, hPGH participates to the control of trophoblast invasiveness and as a PPAR target gene, might be involved in the PPAR-mediated inhibition of trophoblast invasion in an autocrine manner. PAPP-A is a metzincin metalloproteinase that increases in maternal serum during pregnancy. It cleaves the insulinlike growth factor binding protein 4 (IGFBP-4) and consequently modulates the amount of bioactive IGF-II, a factor known to promote trophoblast invasion. The expression of PAPP-A and its regulation by PPAR were studied in vitro using primary cultures of invasive extravillous (EVCT) and endocrine villous (VCT) cytotrophoblasts isolated from the same first trimester chorionic villi. Interestingly, it was shown that invasive EVCT expressed and secreted 10 times more PAPP-A than the endocrine VCT suggesting that PAPP-A might be considered as an early marker of physiological trophoblast invasion. Activation of PPAR inhibited PAPP-A gene expression and secretion specifically in EVCT, whereas it had no effect in VCT [31]. These results suggest that the PPAR-induced decrease in PAPP-A secretion by invasive EVCT might diminish locally the amount of bioactive IGF-II, a factor that promotes trophoblast invasion.
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Fig. (2). A) In vitro models for studying human trophoblast invasion. Human extravillous cytotrophoblasts (EVCT) isolated from first trimester anchoring villi are immunostained using anti-CK7 antibodies and nuclei counter stained with Dapi. For invasion assay, primary EVCT were cultured on Matrigel-coated transwell. Cells invaded the Matrigel and cross the 8 m diameter pores of the membrane as illustrated by scanning electron microscopy. Pseudopodia and cells crossing the porous membrane were quantified and normalized to the number of nuclei after immunostaining with anti-CK7 antibody and counter stained with Dapi. B) EVCT were cultured on matrigel-coated transwells and incubated with increasing concentrations of PPAR agonists rosiglitazone or d15PGJ2 for 48 h. Invasion was quantified as described above and results expressed as number of pseudopodes per number of nuclei relative to control. Results represent the mean ± SD of at least 3 different cultures. * p0.30 g/24 h) during the second trimester. The pathophysiology of preeclampsia is poorly understood but recent experimental data suggest the following sequence of events: 1) poor placental perfusion due to defective invasion and remodeling of the uterine spiral arteries by the EVCT during the first trimester; 2) maternal factors of genetic and/or environmental origin; and 3) oxidative stress secondary to placental ischemia, leading to systemic maternal endothelial dysfunction and clinical signs during the second trimester. The time interval between the cause (defective trophoblastic invasion and remodeling of uteroplacental vasculature during the first trimester) and the consequences (clinical signs during the second trimester) complicates the study of this disorder of placental origin. OXIDIZED LIPIDS AND PREECLAMPSIA Lipid metabolism is profoundly altered during human pregnancy. Plasma triglyceride concentrations [42] and lipid peroxide concentrations in maternal blood increase during pregnancy [43]. This elevation in blood lipid concentrations observed during pregnancy is particularly high in women with pre-eclampsia [44] and might be associated to the characteristic pathologic lesions observed in the uteroplacental bed of preeclamptic patients. The lesion is a necrotizing arteriopathy consisting of fibrinoid necrosis, accumulation of foam cells or lipid-laden macrophages in the decidua, fibroblast proliferation, and a perivascular infiltrate. This lesion, termed “acute atherosis”, resembles endothelial lesions occurring during atherosclerosis, where oxidized low-density lipoprotein (oxLDL) have an important role [45]. It has been reported during pregnancy that LDL, which are involved in the plasma transport of cholesterol are smaller, denser and more susceptible to oxidation [46, 47]. Lipid peroxides are secreted by the human placenta [48] and oxLDL are metabolized by human trophoblasts [49]. To explain the impact of oxidized LDL in preeclampsia, it is necessary to describe the structure and the chemical composition of these lipoproteins. LDL is a spherical particle with a diameter of 22 nm and an average molecular weight of 2.5 million kDa. Neutral lipids such as cholesterol esters and triglycerides form a hydrophobic core, while amphipathic phospholipids and free cholesterol form a surface monolayer and surround the core. The approximate number of molecules of phospholipids, free cholesterol, cholesteryl esters and triglycerides is 700, 600, 1600 and 170 per particle, respectively Fig. (3A). Phospholipids reside in the surface layer of LDL particles and make up 20 to 25% of the whole particle by weight. The most abundant phospholipid in LDL is phosphatidylcholine [50]. Polyunsaturated fatty acids (PUFA) such as linoleic acid, arachidonic acid and docosahexaenoic acid found on phospholipids, cholesteryl esters or triglycerides possess one or more cis- double bond, which is the primary target of oxidation in an LDL particle. The sn-2
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position of the glycerol backbone of phospholipids or the fatty acid esterified on cholesterol are of central importance because they can be linked to a polyunsaturated fatty acyl residue prone to oxidative modification due to the low dissociation energy of the hydrogens of the double allylicactivated methylene group (-CH=CH-CH2-CH=CH-). In phospholipids, the sn-1 position is either linked to an acyl residue via an ester bond (the most abundant) or an alkyl residue via an ether bond (minor compound), whereas the sn2 position contains acyl residues and almost exclusively PUFA [51] such as linoleic and arachidonic acids, which are the targets of free radical attacks (see below). PPAR LIGANDS AT THE MATERNOFETAL INTERFACE Numerous studies identified the ligand-activated nuclear receptor PPAR as a major factor in human trophoblast differentiation, invasion and functions. It therefore raises the question of the nature of the PPAR-natural ligands present at the maternofetal interface. Pregnancy serum was shown to stimulate PPAR in primary and JEG-3 trophoblast cells [52]. Oxidized metabolites of linoleic acid such as 9- and 13hydroxy-octadedienoic acid (HODE) are found in oxLDL and were identified as PPAR specific ligands [53]. In addition, 15- hydroxy-eicosatetraenoic acid (15-HETE) was also shown to activate PPAR in primary human VCT [54]. A main question arises from these experiments: what is the mechanism of production of these oxidized products in LDL? Lipid peroxidation has been the subject of extensive studies and its mechanisms, dynamics and products are now fairly well established. The free radical-mediated peroxidation of lipids has received a great attention in connection with oxidation stress in vivo. The oxidation hypothesis of atherosclerosis has stimulated many studies on the oxidative modification of LDL and focused on lipid peroxidation by non-enzymatic or enzymatic mechanisms. The free radical-mediated peroxidation of PUFA proceeds by five reactions: 1) hydrogen atom transfer from the double allylic-activated methylene group from PUFA to the chain initiating radical or chain carrying peroxyl radicals to give a pentadienyl carbon-centered lipid-radical (L°), 2) reaction of the lipid radical with molecular oxygen to give a lipid peroxyl radical (LOO°), 3) fragmentation of the lipid peroxyl radical to give oxygen and a lipid radical (a reverse reaction of the above reaction), 4) peroxyl radical remove a hydrogen radical from any other activated C-H bond to form a lipid hydroperoxide (LOOH), 5) reduction of the hydroperoxide in the corresponding hydroxide lipid (LOH) by enzyme (peroxidase) [55]. However when a hydrogen donor is not close enough to peroxyl radical, the latter can be rearrange and cyclize. This last reaction is important only for PUFA having more than two double bonds and does not take place for linoleate oxidation (two double bonds). When hydrogen is removed from the double allylicactivated CH2- group from PUFA (Fig (3B)) [56], the resulting mesomeric radical might add oxygen at either of the carbons at the end of this mesomeric system with about equal probability. As a consequence lipid peroxyl radicals
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Fournier et al. Apolipoprotein B
Monolayer shell of phospholipids (~700 molecules)
Unesterified cholesterol (~600 molecules)
Cholesteryl esters (~1600 molecules)
Triacylglycerols (~170 molecules)
HO
B H C5H11
(CH2)7COOH
C5H11
(CH2)7COOH
C5H11 02
02 O
(CH2)7COOH
O
O O
C5H11
(CH2)7COOH
C5H11 + LH -L
+ LH -L HO
(CH2)7COOH
OH O
O
13-HPODE C5H11
(CH2)7COOH
C5H11
9-HPODE (CH2)7COOH
Reduction
Reduction
HO
OH 9-HODE
13-HODE C5H11
(CH2)7COOH
C5H11
(CH2)7COOH
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Fig. (3). Contd…..
C
HO
HO cholesterol
HO
HO
OOH
O 5,6-epoxycholesterol (EPOX)
7-hydroperoxycholesterol (7OOH)
OH HO 7-hydroxycholesterol (7OH)
O 7-ketocholesterol (7K)
Fig. (3). A) Potential oxidation targets in LDL: free and esterified cholesterol, polyunsatuarted fatty acids bound to phospholipids, triacylglycerols containing unsatuarted fatty acids and apolipoprotein B-100. Each LDL particle contains about 7 molecules of -tocopherol and about 2 molecules of carotenoids and ubiquinol (from reference 50). B) Hydrogen removal from linoleic acid and its transformation to a set of two regio-and stereoisomeric LOOH molecules, 13- and 9-HPODE (which are reduced in an enzymatic reaction to the corresponding LOH molecules, 13- and 9-HODE). Radicals remove hydrogen from any double allylic CH2- group in linoleic acid with about equal probability (from reference 56). C) Structure of cholesterol, hydroperoxycholesterol (7OOH), epoxycholesterol (EPOX), hydroxycholesterol (7OH) and ketocholesterol (7K).
are formed, which are stabilized by abstracting a hydrogen atom from another unsaturated acid (LH) forming a LOOH and another L°. Thus a chain reaction is started called “propagation phase” of lipid peroxidation. While linoleic acid generates two regioisomeric hydroperoxides (13hydroperoxy-9,11-octadecadienoic acid, (13-HPODE) and 9hydroperoxy-10,12-octadecadienoic acid, (9-HPODE)), linolenic acid produces four and arachidonic acid six. The carbon carrying the hydroperoxy group is chiral, therefore, each peroxyl is a racemic mixture of two eniantomers [57].
terol thus generating hydroperoxy-derivatives of phospholipids (phosphatidylcholine hydroperoxides, PLOOH) Fig (3B) or of cholesteryl esters (cholesteryl ester hydroperoxides, CEOOH). Fatty acids hydroperoxides in phospholipids are easily reduced to form 13- or 9-HODE Fig (3B). The mechanism of LDL oxidation in vivo is largely a matter of speculation. According to one of the most likely hypothesis lipid peroxidation would begin in PUFA of surface phospholipids, then propagates to the core of the particle and end with oxidation of all lipids.
Althought the propagation of lipid peroxidation is rather well understood there is uncertainty about the mechanism of initiation of the radical chain reaction. The most important system initiating radical chain reaction is hydrogen peroxide or lipid hydroperoxide in the presence of metals (iron or copper ions). These metals cleave these mineral or organic hydroperoxide to radicals (hydroxyl or alkoxyl radicals respectively) and correponding anions in the course of the Fenton reaction [58]. Thus, it is generally admitted that the presence of lipid hydroperoxides molecules and bivalent metal ions are necessary to initiate lipid peroxidation in a non-enzymatic process. Because there are the first products formed during the initial phase of lipid peroxidation, LOOH are called the “primary” products of lipid peroxidation. Hydroperoxide group can be formed either on free PUFA (as described above) or PUFA esterified to glycerol or choles-
Cholesterol (free cholesterol), which is an unsaturated lipid, oxidizes in the same way as an PUFA. The mechanism of sterol oxidation could be described as follow when the LDL oxidation is initiated by copper ions (Cu2+). Initial free radical attack on LDL lipid probably involves abstraction of a bisallylic hydrogen from a PUFA acid esterified on phospholipids, and then subsequent reaction with oxygen to yield the corresponding peroxyl radical. As we mentioned above the resulting peroxyl radical would then be able to abstract another hydrogen from other lipids, including the C7 allylic position of the B-ring of cholesterol to yield the 7hydroperoxycholesterol. The peroxide bond may then undergo cleavage yielding the corresponding cholesterol-7alkoxy radical, which is subject to hydrogen abstraction to form 7-ketocholesterol Fig (3C) [59]. We hypothesized that the lipids constituting oxidatively modified LDL particles in
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Fig. (4). Immunostaining of oxLDL, LOX-1, PPAR and LXRß at the implantation site. Immunohistochemistry was performed on first trimester human placental sections. First trimester placental samples from legal first trimester abortion were obtained after informed consent of the patient. Placental sections were fixed in 4% formalin and then embedded in paraffin. CK7 staining is specific of trophoblasts from extravillous (EVCT) or villous (VCT and ST) origin. OxLDL, the scavenger receptor LOX-1 involved in OxLDL uptake, PPAR and LXRß nuclear receptors were colocalized in EVCT. No staining is observed in control sections incubated with non-immune IgG. SC: stromal core.
blood and/or in the placental bed, might participate in the modulation of trophoblast invasion during the early steps of placental development. The distribution of oxLDL and of the scavenger receptors involved in oxLDL uptake was assessed by immunohistochemistry in sections of first trimester placenta. The presence of both oxLDL and the lectin-like oxidized LDL receptor-1 (LOX-1) was found in cytotrophoblasts of villous and extravillous origin as illustrated in Fig. (4) [60, 61]. The role of oxLDL on trophoblast invasion was studied in vitro using the invasion assay described in Fig. (2). It was observed that oxLDL but not native LDL led to a significant inhibition by about 50% of the trophoblastic cell invasion process Fig. (5A) [60, 62]. The mechanisms by which oxLDL modulate trophoblast invasion were unknown. Therefore, the influence of LDL oxidation state on lipid contents and trophoblast invasion in vitro was investigated. In most cellular experiments, which study the effects of oxLDL, the degree of LDL oxidation has not generally been appreciated. This is particularly relevant when different ratios of Cu2+/LDL are used to mimic LDL oxidation. In the literature, LDL copper-mediated oxidation is classically used to monitor LDL oxidizability, as a possible marker of athero-
sclerosis [63]. Most studies are performed with Cu2+/LDL molar ratios that saturate the Cu2+ binding sites on the apoB100 and follow the time course of LDL oxidation by monitoring the formation of conjugated dienes. These classical LDL oxidative conditions have pointed out the presence of three oxidation phases: the lag phase during which the antioxidant species (-tocopherol and -carotene) are consumed, the propagation phase characterized by a linear formation of lipid peroxidation products (conjugated dienes, LOOH and oxysterols), and the termination phase where conjugated diene concentration is constant. The lipid peroxidation rate depends from experimental conditions such as temperature and copper concentration [64]. This is supported by several studies, which have shown that LDL oxidation by very low or high concentrations of copper led to very different oxidation kinetics characterized by different conjugated diene formations. We have presented in a recent study the extent of LDL oxidation as a function of Cu2+/LDL ratios and have shown that oxidized LDL differs greatly in the nature of lipid peroxidation product. We determined in three conditions of Cu2+/LDL ratios (0.03M, 0.3 μ M and 5 M Cu2+/0.6 μM LDL) and at different times of the conjugated diene formation (termination phase: Tmax, half propagation phase:
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Fig. (5). Effects of oxLDL and their ligands on EVCT invasion in vitro A) Extravillous cytotrophoblast (ECVT) were cultured in Matrigel-coated Transwells, incubated with 50 g/mL native or copper-oxidized LDL (Type A) for 48 h and trophoblastic cell invasion quantified as previously described [60]. Results represent the mean ± SEM of three independent cultures obtained from individual placentas run in triplicate. * P < 0.05, treated vs. controls B) Effects of natural ligands (plain) and synthetic agonists (hatched) of PPAR or LXR on trophoblast invasion in vitro. Cells were incubated for 48 h with 9-HODE (3M), 13-HODE (3M), 15-HETE (3 M), 15d-PGJ2 (10 M), rosiglitazone (1 M), 7-ketocholesterol (7-ketoCH; 1g.L-1) and the LXR agonist T0901317 (5 M) and invasion assays were performed as described. Values represent the mean ± SEM of three independent cultures obtained from individual placentas and run in triplicate. * P < 0.05, treated vs. controls. C) Transcriptionnal activity of the ligand-activated PPAR in EVCT in vitro. EVCT were cotransfected with a plasmid carrying the luciferase coding sequence under the control of a three-repeat sequence of the PPRE and the pCH110 vector encoding ß-galactosidase used as internal transfection control. Cells were cultured in the presence of natural or synthetic PPAR ligands for 18 h, and luciferase activity was measured and normalized to ß-galactosidase activity.
T1/2P) the concentrations of phosphatidylcholine hydroperoxide (PCOOH), cholesteryl ester hydroperoxide (CEOOH) and oxysterols. During oxidation with low concentration of copper and at Tmax, CEOOH and PCOOH are produced and oxysterols are negligible whereas with high copper concentration and at Tmax, oxysterols are the main oxidation products Fig. (6A). Oxidation of apo B was represented by an increasing carbonylation of apo B without any carbonylated fragmentation during LDL oxidation by 0.03 M of copper and at Tmax (type C, Fig. (6B)). In contrast, at 0.3 μM and 5 μM of copper and at Tmax (type B) and T1/2 P, Tmax (type A) respectively, we observed an increase of apo B carbonylation with carbonylated fragmentation (Fig. (6B)). In conclusion, the lipid and protein compositions of oxidized LDL depend strictly on their level of oxidation [62, 65]. Analysis of oxLDL content revealed that only oxLDL containing a high proportion of oxysterols and phosphatidylcholine hydroperoxide derivatives (type A, Tmax), reduced trophoblast invasion [62]. However, during the termination phase (Tmax), hydroperoxy-derivatives of phospholipids or cholesteryl esters are decomposed producing a second generation
of aldehydic and carboxylic compounds in which the carboxylic group is still connected to the glycerol backbone (Fig. (7A)). Among them compounds derived from hydroperoxide of arachidonic acid esterified on phosphatidylcholine were identified as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero3-phosphorylcholine (POVPC) and 1-palmitoyl-2-glutaroylsn-glycero-3-phosphorylcholine (PGPC), Fig. (7B) [66]. In addition to fragmented oxidized diacyl glycerophospholipids another oxidatively fragmented alkylacyl glycerophospholipid of oxLDL is 1-O-hexadecyl-2-azelaoyl-sn-glycero-3phosphocholine (Haz-PC) (Fig. (7C)). It is the main oxidation product of this class of phospholipids in oxidized LDL and a potent PPAR agonist [67]. However we did not find any effect of this compound on trophoblast invasion. We mentioned only three compounds but a large number of bioactive lipid oxidation products have been demonstrated to form in oxLDL and we cannot exclude that other oxidized products are implicated in the reduction of trophoblast invasion. We will not describe all biological oxidized phospholipids products that are generated from phospholipids or cholesteryl esters differing in chemical structure and polarity,
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Fig. (6). Lipid and proteins composition of oxLDL depending on level of oxidation. A) Concentrations of oxysterols (black box), CEOOH (grey box), and PCOOH (open box) in oxLDL (1.5 g/liter total LDL) at the Tmax of oxidation with 0.03 M (type C) and 0.3 M (type B) copper and at the half-time of the propagation phase (T1/2P) and the termination phase (Tmax) of oxidation with 5 M copper (type A). Oxysterols, CEOOH, and PCOOH were isolated after extracting lipids from oxLDL, measured by gas chromatography for oxysterols, separated by HPLC, and measured by chemiluminescence for CEOOH and PCOOH. B) Western blot analysis of apo B from copper oxLDL, at T1/2P and Tmax for LDL oxidized with 5 M (type A) copper and at Tmax for LDL oxidized with 0.3 M (type B) or 0.03 M (type C) copper. Carbonylated apo B, carbonylated apo B fragments, and irradiated ovalbumin were derivatized with DNPH and were detected by an immunoassay with antidinitrophenyl antibodies (from reference 65).
many reviews have been published on this field [68-71] and other potential ligands of PPAR might contribute to their biologic effects. Among these ligands, phosphatidylcholine hydroperoxide derivatives provide PPAR ligands such as HETE and HODE. It was shown that potential PPAR ligands such as 15-HETE or 9-HODE and 13-HODE inhibited trophoblast invasion (Fig. (5B)) [62] and we demonstrate here in that 15-HETE and 9-HODE activated the transcription of the reporter gene luciferase under the control of three PPAR-response elements (PPRE) (Fig. (5C)). Accordingly, Schild et al. [54] reported that 15-HETE, 9-HODE and 13-HODE activated PPAR in villous cytotrophoblasts, resulting in enhanced hCG production, a marker of villous cytotrophoblast differentiation. Biological oxidized phospholipids products that are generated from phospholipids or cholesteryl esters can also provide oxysterols such as 7 ketocholesterol, a natural ligand to another nuclear receptor, the liver X receptor (LXR) that also heterodimerize with RXR. LXR regulates genes controlling lipid metabolism and is
expressed in liver, kidney, intestine and spleen [72]. As described for PPAR activation of RXR/LXRß heterodimers with specific natural or synthetic LXR ligands markedly inhibit human trophoblast invasion in vitro (Fig. (5B)), demonstrating for the first time the role of this nuclear receptor in the modulation of human trophoblast invasion [62]. The clinical relevance of these in vitro findings was enforced by the coimmunodetection in situ of oxLDL, the scavenger receptor LOX-1 involved in oxLDL uptake, and the two nuclear receptors PPAR and LXRß in invasive EVCT at the maternofetal interface (Fig. (4)) [60]. In conclusion, our results clearly indicate that oxLDL predominantly composed of oxysterols, CEOOH and PCOOH, abrogate the invasive properties of human EVCT in vitro, probably through LOX-1-mediated uptake. Oxysterols, CEOOH and PCOOH provide ligands for PPAR and LXR and we demonstrated that activation of these two nuclear receptors inhibit trophoblast invasion by regulating expression of factors produced by the EVCT and involved in the
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A
O
O
O
CH3
O
O
O N
P
O
CH3 CH3
O
O OH
18:2 cholesteryl Ester
16:0-18:2 PtdCho
OOH
O
O O O CH3
O 18:2 cholesteryl Ester Hydroperoxide
OOH
O N
P
O
CH3 CH3
O
O OH
16:0-18:2 PtdCho Hydroperoxide
O O
O O 9:0 Ald Cholesteryl Ester Core aldehyde O O
CH3
O
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P
O
O
O OH
16:0-9:0 Ald PCho Core Aldehyde
CH3 CH3
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Fig. (7). Contd…..
N
B O
HO
P
O
O
O O O O OHC
POVPC
N O
-O
P O
O O
O O O HOOC
POVPC
C
O HO
O
O O
O O
OH P
O
N
Fig. (7) A) Oxidation products of oxidized cholesteryl ester (18:2 cholesteryl ester: cholesterol linoleate; 9:0 Ald cholesteryl ester: cholesterol nonanal; 16:0-9:0 aldehyde PCho: 1-palmitoyl-2-nonanal-sn-glycero-3-phosphocholine). B) Oxidation products of oxidized phospholipids (POVPC, PGPC). C) Oxidation product of oxidized alkyl phospholipids (Haz-PC).
invasion process (61). This study improves our understanding of preeclampsia, a condition in which lipid peroxidation is increased and trophoblast invasion is defective.
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ACKNOWLEDGMENTS
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We thank the Department of Obstetrics and Gynecology at the Broussais Hospitals, Paris, France for providing placental tissues and Dr Tatsuya Sawamura for LOX-1 antibody. This work was supported by “la Caisse d’Assurance Maladie des Professions Libérales-Province”, CAMPLP, Paris la Défense, 92042, France.
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Received: August 18, 2008
Revised: September 26, 2008
Accepted: October 07, 2008
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