Published online before print December 22, 2008, doi: 10.1161/HYPERTENSIONAHA.108.122630
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2009;53:270.)
© 2009 American Heart Association, Inc.
Original Articles |
Increased Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Expression in the Maternal Vasculature of Women With Preeclampsia
Role for Peroxynitrite
From the Departments of Obstetrics and Gynaecology (S.S., Y.X., S.T.D.) and Physiology (S.S., Y.X., S.T.D.) and Cardiovascular Research Group and Women and Children’s Health Research Institute (S.T.D.), University of Alberta, Edmonton, Alberta, Canada; and Vascular Physiology (T.S.), National Cardiovascular Center Research Institute, Osaka, Japan.
Correspondence to Sandra T. Davidge, Departments of Ob/Gyn and Physiology, 232 HMRC, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail sandra.davidge{at}ualberta.ca
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Preeclampsia is a hypertensive disorder unique to pregnancy, in which the placenta may release factors into the maternal circulation resulting in systemic effects. Small dense low-density lipoprotein (LDL; which is susceptible for oxidation) is increased in preeclampsia. Lectin-like oxidized LDL receptor-1 (LOX-1) is a receptor for oxidized LDL. However, the expression levels and the regulation of LOX-1 in the maternal vasculature of women with preeclampsia are unknown. We hypothesized that there is an increased LOX-1 expression in arteries from women with preeclampsia. We further hypothesized that circulating factors in the plasma of women with preeclampsia would upregulate the LOX-1 expression in vascular endothelial cells and contribute to vascular endothelial oxidative stress. We observed abundant LOX-1 expression and the presence of oxidized LDL in arteries from women with preeclampsia, which was negligible in arteries from normotensive pregnant women. Human umbilical vein endothelial cells treated for 24 hours with 2% plasma from preeclamptic women increased LOX-1 expression and oxidized LDL uptake, as well as induced oxidative stress, as evidenced by increased NADPH oxidase activity and superoxide and peroxynitrite levels. These effects were significantly reduced by pretreatment with blocking antibody or small interfering RNA to LOX-1, as well as 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III), chloride (FeTPPS), a peroxynitrite scavenger. Exogenous peroxynitrite and 3-morpholino sydnonimine (SIN-1) increased LOX-1 protein and mRNA expression. In conclusion, increased LOX-1 expression in the systemic vasculature of preeclampsia women provides a fundamental insight into the pathology of preeclampsia and likely contributes to the induction and maintenance of vascular oxidative stress.
Key Words: preeclampsia • LOX-1 • NADPH oxidase • endothelium • peroxynitrite
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Preeclampsia is a pregnancy-specific disorder in humans, characterized by hypertension and proteinuria occurring after the 20th week of gestation. These symptoms resolve after delivery, suggesting that the placenta plays a central role in the pathogenesis of this disorder. It is generally agreed that poor invasion of the uterine spiral arteries by the trophoblast leads to an ischemic placenta that subsequently releases a number of circulating factors into the maternal circulation.1 The factors released into the maternal circulation include a number of vasoactive molecules and proinflammatory cytokines, which can potentially cause dysfunction of the maternal endothelium. Such factors can induce the endothelial cells to generate excess of oxygen-derived free radicals, resulting in the development of oxidative stress.2
One of the early changes that may occur as a result of endothelial injury in the uterine spiral arteries is the accumulation of neutral lipids, a phenomenon called "acute atherosis" of pregnancy.3 Whether lipid accumulation occurs in the maternal systemic vasculature and, if so, the possible mechanisms involved remain unknown. Several studies have shown increased serum levels of triglycerides, low-density lipoproteins (LDLs), and lipid peroxides in women with preeclampsia when compared with normotensive pregnant women.4,5 In addition, small dense LDL is also increased in the plasma of women with preeclampsia.6 Small dense LDLs are more susceptible to oxidation, resulting in the generation of oxidized LDL (oxLDL).7,8 OxLDL can bind to the lectin-like oxidized LDL receptor-1 (LOX-1) on endothelial cells.9 LOX-1 is a type II membrane protein cell surface receptor identified on endothelial cells, vascular smooth muscle cells, and monocyte macrophages. LOX-1 is expressed in atherosclerotic lesions in humans10 and has also been shown to be elevated in hypertensive rats.11 LOX-1 is responsible for the binding, uptake, and degradation of oxLDL. During this process, the binding of oxLDL activates the NADPH oxidase enzyme system, resulting in the excessive generation of superoxide.12 Scavenging of NO by superoxide may not only reduce NO bioavailability but also generate a more potent oxidant, peroxynitrite. Peroxynitrite formation has been observed in both the placenta13 and the maternal vasculature of women with preeclampsia.14 One recent study has observed elevated LOX-1 expression in the placenta of women with preeclampsia.15 However, the expression, regulation, and significance of LOX-1 in the maternal systemic vasculature of preeclampsia remain unknown.
We hypothesized that LOX-1 is upregulated in small resistance-sized arteries obtained from women with preeclampsia. We further hypothesized that the circulating factors in the plasma of women with preeclampsia via the formation of peroxynitrite provide a feed-forward loop to upregulate LOX-1.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
Pregnant subjects were recruited at the time of delivery, and nonpregnant subjects were recruited at the time of abdominal surgeries at the Royal Alexandra Hospital (Edmonton, Canada). The protocols were approved by the University of Alberta Ethics Committee, and the studies were conducted according to the principles of the Declaration of Helsinki and Title 45, US Code of Federal Regulations, Part 46, Protection of Human Subjects, Revised November 13, 2001, effective December 13, 2001. All of the subjects provided informed consent before inclusion in the study. Twelve subjects had preeclampsia characterized by the de novo onset of hypertension and proteinuria after the 20th week of gestation. Hypertension was defined as a blood pressure of >140/90 mm Hg on 2 occasions 6 hours apart and proteinuria of >500 mg in a 24-hour urine collection or more than +2 on a dip stick.14 Normal pregnant subjects (n=12) were normotensive throughout pregnancy. Nonpregnant subjects (n=12) were also normotensive. None of the subjects had a past history of chronic hypertension, renal, liver, or other metabolic diseases and were not on any medications. Either blood samples at the time of admission or fat biopsies during surgeries were collected from these women as detailed below. Blood was collected by routine forearm venipuncture at the time of admission (before delivery) in tubes containing EDTA. Blood samples were immediately centrifuged at 2000g for 20 minutes and then aliquoted under sterile conditions and stored at –80°C. Omental fat biopsies were obtained at the time of cesarean section for normotensive pregnant and preeclamptic women or during abdominal surgeries for nonpregnant women who were admitted for indications such as dysfunctional uterine bleeding, ovarian cyst, menorrhagia, and dysmenorrhea and then snap frozen in liquid nitrogen and stored at –80°C.14 The patient characteristics are shown on Tables S1 and S2 (see online data supplement at http://hyper.ahajournals.org). In the nonpregnant group, all of the subjects were white, nonsmokers, not previously pregnant, and not on any medications.
Immunohistochemistry
Our first aim was to compare the expression of LOX-1 and to detect the presence of oxLDL in small arteries from nonpregnant, pregnant, and preeclamptic women. Omental fat biopsies were flash frozen in liquid nitrogen and stored at –80°C. Later they were cut into 
0.5-cm diameter in size and frozen in optimal cutting temperature compound, cut into 8-µm sections, mounted on glass slides at –25°C, and stored at –80°C until use. All of the arteries in the section were counted. The slides were immunostained using rabbit polyclonal antibodies for LOX-1 (1:100; Santa Cruz Biotechnologies) and oxLDL (1:100; Calbiochem). Antirabbit secondary antibody (1: 200; Alexa fluor 488, Invitrogen) was used to detect the primary antibody and was visualized using a fluorescein isothiocyanate filter.
To address the mechanisms of LOX-1 upregulation, we performed a bioassay by observing the effects of plasma from the 3 groups of women on endothelial cells in culture. Human umbilical vein endothelial cells were treated with 2% plasma from nonpregnant, pregnant, and preeclamptic women for 24 hours. Individual plasma samples but not pooled plasma from each group were used in this study. In response to treatment with plasma, DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate)- labeled oxLDL uptake, intracellular superoxide levels using dihydroethidine, NADPH oxidase activity by lucigenin chemiluminescence, and nitrotyrosine staining as a marker of peroxynitrite formation were measured. In some experiments, cells treated with plasma were pretreated with 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III), chloride (FeTPPS; 5 µmol/L), a peroxynitrite scavenger; monoclonal antibody to LOX-1 (mAbLOX-1; 10 µg/mL); or small interfering RNA (siRNA; 30 nmol/L) to LOX-1 before exposure to plasma. In a separate set of experiments, human umbilical vein endothelial cells were treated with either 3-morpholino sydnonimine (SIN-1; 0.25 mmol/L) or peroxynitrite (25 µmol/L) for 6 hours. LOX-1 protein and mRNA expressions were assessed by Western blot and PCR, respectively. Please see the online data supplement for detailed methods used in this study.
Statistical Analysis
Values are expressed as means±SEMs. Comparison of 
3 groups was done using a 1-way ANOVA followed by a Tukey’s posthoc test. Comparison of 2 groups was conducted using a Student t test. A P value of <0.05 was deemed significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Arterial Expression of LOX-1 and OxLDL
We detected abundant LOX-1 expression (P<0.001) in arteries from women with preeclampsia (15.00±6.50 arbitrary units [AU]), whereas there was negligible expression in arteries from nonpregnant (0.18±0.09 AU) and pregnant women (0.25±0.22 AU; Figure 1). In arteries from preeclamptic women, LOX-1 expression was localized to both the endothelium and the vascular smooth muscle cells. However, LOX-1 expression is greater in the endothelial layer.
|
Because LOX-1 is involved in the binding and uptake of oxLDL, we performed immunohistochemistry to identify the presence of oxLDL in these arteries. OxLDL was present only in arteries from women with preeclampsia (6.00±0.50 AU; P<0.001) but not in arteries from nonpregnant and pregnant women (0.07±0.02 and 0.07±0.06 AU; Figure 1). Also, OxLDL appears to accumulate immediately beneath the endothelial layer.
Endothelial Response to Plasma
LOX-1 Expression in Response to Plasma
LOX-1 expression was significantly increased in endothelial cells exposed to plasma from women with preeclampsia (0.419±0.018 AU; P<0.01) in comparison with cells treated with plasma from nonpregnant and pregnant women (0.1450±0.0039 and 0.1930±0.0053 AU), respectively (Figure 2).
|
DiI-Labeled OxLDL Uptake
We observed significantly increased oxLDL uptake by endothelial cells in response to treatment with preeclamptic plasma when compared with treatment with nonpregnant and pregnant plasma. This uptake of oxLDL was significantly reduced by competition with unlabeled oxLDL and mAbLOX-1 (Figure 3).
|
NADPH Oxidase Activity
NADPH oxidase activity was significantly increased in endothelial cells treated for 24 hours with plasma from women with preeclampsia (53.92±1.40 AU/mg of protein; P<0.01) when compared with treatment with plasma from nonpregnant and pregnant women (31.37±1.10 and 29.60±1.20; AU/mg of protein), respectively (Figure 4A). LOX-1 blockade with mAbLOX-1 caused a marked reduction in NADPH oxidase activity only in the preeclamptic group (24.70±1.05 AU/mg of protein; P<0.01) but did not significantly affect NADPH oxidase activity in the nonpregnant and pregnant groups (26.58±1.50 and 26.10±1.30 AU/mg of protein, respectively). An isoimmune IgG control did not affect the NADPH oxidase activity in endothelial cells in response to preeclamptic plasma. These results were also confirmed by using siRNA to LOX-1 preeclamptic, which reduced preeclamptic plasma-induced NADPH oxidase activity to 25.90±0.50 AU/mg of protein (Figure 4B).
|
In a separate set of experiments, LOX-1 expression and NADPH oxidase activity in endothelial cells in response to plasma were assessed at a time point (6 hours) before LOX-1 expression was increased. Although LOX-1 expression did not change at 6 hours (data not shown), NADPH oxidase activity was increased significantly (P<0.05) in the preeclamptic group as early as 6 hours (11.21±1.00 AU/mg of protein) in comparison with nonpregnant (8.30±1.00 AU/mg of protein) and pregnant (8.10±1.00 AU/mg of protein) groups. Furthermore, mAbLOX-1 also reduced this increase in NADPH oxidase activity (8.40±1.00 AU/mg of protein; P<0.05) in response to preeclamptic plasma. These results suggest that increased plasma levels of ligands to LOX-1 are responsible for this early increase in NADPH oxidase activity, although at a later time point (24 hours), the increased NADPH oxidase was likely attributable to increases in both LOX-1 expression and the higher levels of ligands in the preeclamptic plasma.
Superoxide Detection in Live Cells
Endothelial cells treated with plasma from women with preeclampsia generated significantly high levels of superoxide (1.309±0.032 AU; P<0.01) when compared with treatment with plasma from nonpregnant (0.574±0.027 AU) and pregnant (0.265±0.019 AU) women (Figure 5). This increase in superoxide generation in response to preeclamptic plasma was reduced by pretreatment with 
-carrageenan (0.445±0.018 AU), a nonspecific LOX-1 blocker; mAbLOX-1 (0.649±0.023 AU), a specific monoclonal blocking antibody to LOX-1; and NADPH oxidase inhibitors apocynin (0.629±0.017 AU) and diphenylene iodonium chloride (0.0676±0.027 AU). Endothelial cells treated with superoxide dismutase were used as a negative control (data not shown).
|
Detection of Nitrotyrosine as a Marker of Peroxynitrite
Endothelial cells treated with plasma from women with preeclampsia (18.769±4.022 AU; P<0.01) showed enhanced nitrotyrosine formation when compared with endothelial cells treated with plasma from nonpregnant and pregnant women (1.016±0.132 and 0.722±0.106 AU), respectively (Figure 6). Also, mAbLOX-1 and siRNA to LOX-1 reduced preeclamptic plasma–induced nitrotyrosine levels significantly (10.347±0.580 and 09.633±0.639 AU, respectively; P<0.05). Also, FeTPPS almost completely abolished (0.762±0.051 AU) the generation of superoxide by endothelial cells in response to plasma from women with preeclampsia.
|
Effect of Peroxynitrite on LOX-1 Expression
Having observed increased peroxynitrite generation in endothelial cells treated with plasma from women with preeclampsia, we sought to determine whether peroxynitrite plays a role in the upregulation of LOX-1 in response to plasma. LOX-1 expression was assessed by Western blot, in response to preeclamptic plasma in the presence of FeTPPS, a peroxynitrite scavenger. Interestingly, FeTPPS, significantly reduced LOX-1 expression by 30% (P<0.05), suggesting that peroxynitrite may play a role in inducing LOX-1 in preeclampsia (Figure 7).
|
In a separate series of experiments, we observed that exogenous peroxynitrite induced a modest but significant increase in LOX-1 protein expression by 40% (Figure 8A). This was also confirmed by using SIN-1, an agent that generates endogenous peroxynitrite by increasing both NO and superoxide production. SIN-1 also increased LOX-1 protein expression (Figure 8B; P<0.05). We also determined whether peroxynitrite can upregulate LOX-1 mRNA. We assessed LOX-1 mRNA expression in response to peroxynitrite or SIN-1. Both peroxynitrite and SIN-1 induced a 1.5-fold (P<0.05) increase in LOX-1 mRNA expression in 6 hours (Figure 8C and 8D).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In women with preeclampsia, there is evidence for focal accumulation of lipid-laden macrophages in decidual vessels16 and accumulation of neutral lipids in uterine spiral arteries.3 These phenomena have been termed "acute atherosis," which is analogous to atherosclerosis. However, reports of such vascular abnormalities in the maternal systemic vasculature have not been described. In the present study, we report for the first time the accumulation of oxLDL and increased LOX-1 expression in the maternal vasculature of women with preeclampsia. Our data also indicate that peroxynitrite generated secondary to LOX-1 upregulation, in turn, provides a feed-forward loop to further increase LOX-1 in preeclampsia. In women destined to develop preeclampsia, the symptoms continue to progress until delivery, suggesting a feed-forward mechanism of vascular endothelial dysfunction that could be possibly mediated by peroxynitrite through LOX-1 pathway.
Preeclampsia is characterized by hyperlipidemia,4,5 including alterations in LDL. For instance, small dense LDLs are significantly elevated in the circulation of women with preeclampsia.5,6 These small dense LDL particles are more atherogenic7 and are more susceptible for oxidative modification,4,7,17 resulting in the formation of oxLDL. OxLDL is immunogenic and subsequently results in the formation of autoantibodies to oxLDL in the circulation.18 Thus, circulating autoantibodies to oxLDL have also provided evidence for the presence of oxLDL. Data from a previous study has shown increased levels of autoantibodies to oxLDL in the circulation of women with preeclampsia.19 In contrast, however, other studies have reported no change in levels of autoantibodies to oxLDL in the plasma of women with preeclampsia.20–22 In addition, another recent study has shown decreased plasma levels of oxLDL in preeclamptic women, which the authors suggested could be attributed to increased levels of autoantibody to oxLDL.23 It has also been shown that women with increased circulating levels of oxLDL have a significantly higher risk for developing preeclampsia.24,25 Thus, the data regarding circulating oxLDL or its autoantibodies have shown evidence to suggest increased circulating levels of oxLDL in preeclamptic women; however, some of the data are conflicting. Our data provide the first direct evidence for the presence of increased oxLDL that has accumulated within the vasculature of women with preeclampsia.
The possible mechanisms by which oxLDL accumulates in the vasculature of women with preeclampsia and their consequences have not been described previously. It is known that oxLDL binds to LOX-1 on vascular cells, including endothelial cells and smooth muscle cells. LOX-1 is a major endothelial receptor for the uptake of 50% to 70% of oxLDL.26 In the present study, we found enhanced expression of LOX-1 primarily in the endothelial cell layer of the small arteries in women with preeclampsia. This could lead to the enhanced uptake and accumulation of oxLDL in the arterial walls, which could have deleterious effects by inducing and maintaining oxidative stress that may subsequently lead to endothelial cell dysfunction.
Binding of oxLDL to LOX-1 could activate the NADPH oxidase enzyme system to generate superoxide.12 We demonstrated increased NADPH oxidase activity in cultured endothelial cells in response only to plasma from women with preeclampsia, which was significantly reduced by blocking with mAbLOX-1 or siRNA to LOX-1. This suggests that ligands to LOX-1, possibly oxLDL, play a role in upregulating the NADPH oxidase enzyme system specifically in preeclampsia. To further address whether the increased NADPH oxidase activity and the observed increase in superoxide levels were attributable not only to increased LOX-1 expression but also to increased levels of ligands circulating in the plasma, we examined LOX-1 protein expression and NADPH oxidase activity at an earlier time point (6 hours) before LOX-1 expression was induced. We found that, despite normal LOX-1 expression in response to plasma from 3 groups of women at 6 hours, NADPH oxidase activity was increased significantly only in the preeclamptic group, suggesting that initial increases in superoxide levels might stem from increased circulating levels of ligands to LOX-1. Long-term increases in NADPH oxidase and subsequent superoxide levels could be a combined effect of both increases in oxLDL levels and increased LOX-1 expression, as seen in our 24-hour experimental protocol.
In this study, we have also shown a novel pathway for the regulation of LOX-1 by peroxynitrite. Peroxynitrite increased both LOX-1 mRNA and protein expression. Furthermore, we have demonstrated a feed-forward loop by which peroxynitrite further upregulates and maintains a higher LOX-1 expression. Thus, it appears that generation of peroxynitrite through LOX-1 further upregulates LOX-1 and may be a key player in perpetuating oxidative stress in preeclampsia. Indeed, blocking LOX-1 in endothelial cells in response to preeclamptic plasma significantly reduced superoxide and peroxynitrite levels.
Other than peroxynitrite, LOX-1 can be upregulated by a number of factors in the plasma, such as tumor-necrosis factor-
, transforming growth factor-β, oxLDL, angiotensin II, endothelin I, C-reactive protein, and 8-isoprostane, to mention a few.27 Many of these factors have been shown to be elevated in the plasma of women with preeclampsia2; thus, the upregulation of LOX-1 and activation of NADPH oxidase could be through the action of multiple factors. In our experiments, mAbLOX-1 reduced NADPH oxidase activity by >50%, suggesting that this receptor could be a major factor for inducing oxidative stress in preeclampsia. Moreover, apocynin, an NADPH oxidase inhibitor, reduced superoxide generation in response to preeclamptic plasma to the same extent as mAbLOX-1, suggesting that most of the NADPH oxidase activity in preeclampsia could be through LOX-1, as demonstrated in this bioassay. This does not exclude the role of other factors in activating the NADPH oxidase enzyme system, because mAbLOX-1 did not completely suppress NADPH oxidase activity. Importantly, apart from oxLDL, there is an array of structurally different, negatively charged molecules, such as polyanionic chemicals (polyinosinic acid and carrageenan), anionic phospholipids (phosphatidylserine and phosphatidylinositol), and cellular ligands, such as apoptotic/aged cells, activated platelets, and bacteria, that can act as ligands for LOX-1.27,28 Although this study did not focus on the ligands, but on the receptor itself, it is possible that multiple factors could be involved in the activation of LOX-1, thus having broad implications for a common mechanism for vascular dysfunction in women with preeclampsia.
Because of the heterogeneity of preeclampsia, different circulating factors could play a role in different women or during different stages of the disease process. Nonetheless, LOX-1 pathway appears to be a predominant pathway in inducing cellular oxidative stress in response to circulating factors in the plasma of women with preeclampsia. Moreover, because the effect of a number of circulating factors converges on LOX-1 pathway, LOX-1 could be a potential target for therapeutic intervention.
Finally, preeclampsia is often considered the extreme of a pregnancy continuum, with evidence of inflammation and oxidative stress increased in pregnancy when compared with the nonpregnant state.29 However, in our study, the responses in the nonpregnant and the pregnant groups were similar in most of the outcome measures in the vasculature and in isolated endothelial cells. However, the levels of superoxide were in fact reduced in endothelial cells treated with pregnant plasma relative to nonpregnant plasma. Thus preeclampsia, in part, could be a lack of adaptation to pregnancy, in addition to circulating factors that activate the endothelium.
Perspectives
Preeclampsia is likely a multifactorial disorder, with inflammation, oxidative stress, immune mechanisms, and other pathways playing a role. Although a number of studies have clearly shown evidence for vascular oxidative stress in preeclampsia,14,30–32 the antioxidant trials with vitamins C and E have failed to reduce the incidence of preeclampsia33 and in some cases have even been detrimental by increasing the rate of low birth weight babies.34 These antioxidants are designed to scavenge oxidants and not to inhibit generation of such molecules. Furthermore, they would not provide the first line of defense in scavenging intracellular superoxide. In light of such evidence, identification of pathways, such as LOX-1, that could be blocked may prove to be more effective in reducing intracellular oxidative stress. Our study clearly suggests that LOX-1 pathway could be a major pathway involved in promoting and maintaining a vicious cycle of events resulting in oxidative stress and ultimately leading to endothelial cell dysfunction in preeclampsia.
|
Acknowledgments |
|---|
We thank Donna Dawson from the Royal Alexandra Hospital for sample collection.
Sources of Funding
This work was supported by grants from the Canadian Institutes for Health Research. S.S. was supported by the Maternal-Fetal-Newborn Health and Strategic Training Initiative in Research in Reproductive Health Sciences Training Programs of the Canadian Institutes for Health Research, the Alberta Heritage Foundation for Medical Research, and the Junior Personnel Award from the Heart and Stroke Foundation of Canada. S.T.D. is an Alberta Heritage Foundation for Medical Research Scientist and a Canada Research Chair in Women’s Cardiovascular Health.
Disclosures
None.
|
Footnotes |
|---|
*Deceased.
Received September 3, 2008; first decision October 8, 2008; accepted November 24, 2008.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA. Pathophysiology of preeclampsia: linking placental ischemia/hypoxia with microvascular dysfunction. Microcirculation. 2002; 9: 147–160.[CrossRef][Medline] [Order article via Infotrieve]
2. Sankaralingam S, Arenas IA, Lalu MM, Davidge ST. Preeclampsia: current understanding of the molecular basis of vascular dysfunction. Expert Rev Mol Med. 2006; 8: 1–20.[Medline] [Order article via Infotrieve]
3. De Wolf F, Brosens I, Robertson WB. Ultrastructure of uteroplacental arteries. Contrib Gynecol Obstet. 1982; 9: 86–99.[Medline] [Order article via Infotrieve]
4. Potter JM, Nestel PJ. The hyperlipidemia of pregnancy in normal and complicated pregnancies. Am J Obstet Gynecol. 1979; 133: 165–170.[Medline] [Order article via Infotrieve]
5. Hubel CA, Lyall F, Weissfeld L, Gandley RE, Roberts JM. Small low-density lipoproteins and vascular cell adhesion molecule-1 are increased in association with hyperlipidemia in preeclampsia. Metabolism. 1998; 47: 1281–1288.[CrossRef][Medline] [Order article via Infotrieve]
6. Sattar N, Bendomir A, Berry C, Shepherd J, Greer IA, Packard CJ. Lipoprotein subfraction concentrations in preeclampsia: pathogenic parallels to atherosclerosis. Obstet Gynecol. 1997; 89: 403–408.[CrossRef][Medline] [Order article via Infotrieve]
7. Wakatsuki A, Ikenoue N, Okatani Y, Shinohara K, Fukaya T. Lipoprotein particles in preeclampsia: susceptibility to oxidative modification. Obstet Gynecol. 2000; 96: 55–59.[CrossRef][Medline] [Order article via Infotrieve]
8. Witztum JL. Susceptibility of low-density lipoprotein to oxidative modification. Am J Med. 1993; 94: 347–349.[CrossRef][Medline] [Order article via Infotrieve]
9. Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, Tanaka T, Miwa S, Katsura Y, Kita T, Masaki T. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997; 386: 73–77.[CrossRef][Medline] [Order article via Infotrieve]
10. Kataoka H, Kume N, Miyamoto S, Minami M, Moriwaki H, Murase T, Sawamura T, Masaki T, Hashimoto N, Kita T. Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation. 1999; 99: 3110–3117.
11. Nagase M, Hirose S, Sawamura T, Masaki T, Fujita T. Enhanced expression of endothelial oxidized low-density lipoprotein receptor (LOX-1) in hypertensive rats. Biochem Biophys Res Commun. 1997; 237: 496–498.[CrossRef][Medline] [Order article via Infotrieve]
12. Cominacini L, Rigoni A, Pasini AF, Garbin U, Davoli A, Campagnola M, Pastorino AM, Lo Cascio V, Sawamura T. The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide. J Biol Chem. 2001; 276: 13750–13755.
13. Myatt L, Rosenfield RB, Eis AL, Brockman DE, Greer I, Lyall F. Nitrotyrosine residues in placenta. Evidence of peroxynitrite formation and action. Hypertension. 1996; 28: 488–493.
14. Roggensack AM, Zhang Y, Davidge ST. Evidence for peroxynitrite formation in the vasculature of women with preeclampsia. Hypertension. 1999; 33: 83–89.
15. Lee H, Park H, Kim YJ, Kim HJ, Ahn YM, Park B, Park JH, Lee BE. Expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in human preeclamptic placenta: possible implications in the process of trophoblast apoptosis. Placenta. 2005; 26: 226–233.[CrossRef][Medline] [Order article via Infotrieve]
16. Sheppard BL, Bonnar J. An ultrastructural study of utero-placental spiral arteries in hypertensive and normotensive pregnancy and fetal growth retardation. Br J Obstet Gynaecol. 1981; 88: 695–705.[Medline] [Order article via Infotrieve]
17. Davidge ST, Hubel CA, Brayden RD, Capeless EC, McLaughlin MK. Sera antioxidant activity in uncomplicated and preeclamptic pregnancies. Obstet Gynecol. 1992; 79: 897–901.[Medline] [Order article via Infotrieve]
18. Horkko S, Binder CJ, Shaw PX, Chang MK, Silverman G, Palinski W, Witztum JL. Immunological responses to oxidized LDL. Free Radic Biol Med. 2000; 28: 1771–1779.[CrossRef][Medline] [Order article via Infotrieve]
19. Branch DW, Mitchell MD, Miller E, Palinski W, Witztum JL. Pre-eclampsia and serum antibodies to oxidised low-density lipoprotein. Lancet. 1994; 343: 645–646.[CrossRef][Medline] [Order article via Infotrieve]
20. Armstrong VW, Wieland E, Diedrich F, Renner A, Rath W, Kreuzer H, Kuhn W, Oellerich M. Serum antibodies to oxidised low-density lipoprotein in pre-eclampsia and coronary heart disease. Lancet. 1994; 343: 1570.[CrossRef][Medline] [Order article via Infotrieve]
21. Gratacos E, Casals E, Deulofeu R, Gomez O, Cararach V, Alonso PL, Fortuny A. Serum antibodies to oxidized low-density lipoprotein in pregnant women with preeclampsia and chronic hypertension: lack of correlation with lipid peroxides. Hypertens Pregnancy. 2001; 20: 177–183.[CrossRef][Medline] [Order article via Infotrieve]
22. Jain M, Sawhney H, Aggarwal N, Vashistha K, Majumdhar S. Auto antibodies against oxidized low density lipoprotein in severe preeclampsia. J Obstet Gynaecol Res. 2004; 30: 188–192.[Medline] [Order article via Infotrieve]
23. Raijmakers MT, van Tits BJ, Hak-Lemmers HL, Roes EM, Steegers EA, Peters WH. Low plasma levels of oxidized low density lipoprotein in preeclampsia. Acta Obstet Gynecol Scand. 2004; 83: 1173–1177.[Medline] [Order article via Infotrieve]
24. Qiu C, Phung TT, Vadachkoria S, Muy-Rivera M, Sanchez SE, Williams MA. Oxidized low-density lipoprotein (oxidized LDL) and the risk of preeclampsia. Physiol Res. 2006; 55: 491–500.[Medline] [Order article via Infotrieve]
25. Sanchez SE, Williams MA, Muy-Rivera M, Qiu C, Vadachkoria S, Bazul V. A case-control study of oxidized low density lipoproteins and preeclampsia risk. Gynecol Endocrinol. 2005; 21: 193–199.[Medline] [Order article via Infotrieve]
26. Yamada Y, Doi T, Hamakubo T, Kodama T. Scavenger receptor family proteins: roles for atherosclerosis, host defence and disorders of the central nervous system. Cell Mol Life Sci. 1998; 54: 628–640.[CrossRef][Medline] [Order article via Infotrieve]
27. Chen M, Masaki T, Sawamura T. LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther. 2002; 95: 89–100.[CrossRef][Medline] [Order article via Infotrieve]
28. Oka K, Sawamura T, Kikuta K, Itokawa S, Kume N, Kita T, Masaki T. Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proc Natl Acad Sci U S A. 1998; 95: 9535–9540.
29. Sacks GP, Studena K, Sargent K, Redman CW. Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol. 1998; 179: 80–86.[CrossRef][Medline] [Order article via Infotrieve]
30. Hubel CA, Kagan VE, Kisin ER, McLaughlin MK, Roberts JM. Increased ascorbate radical formation and ascorbate depletion in plasma from women with preeclampsia: implications for oxidative stress. Free Radic Biol Med. 1997; 23: 597–609.[CrossRef][Medline] [Order article via Infotrieve]
31. Llurba E, Gratacos E, Martin-Gallan P, Cabero L, Dominguez C. A comprehensive study of oxidative stress and antioxidant status in preeclampsia and normal pregnancy. Free Radic Biol Med. 2004; 37: 557–570.[CrossRef][Medline] [Order article via Infotrieve]
32. Wang YP, Walsh SW, Guo JD, Zhang JY. The imbalance between thromboxane and prostacyclin in preeclampsia is associated with an imbalance between lipid peroxides and vitamin E in maternal blood. Am J Obstet Gynecol. 1991; 165: 1695–1700.[Medline] [Order article via Infotrieve]
33. Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med. 2006; 354: 1796–1806.
34. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet. 2006; 367: 1145–1154.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  S. Sankaralingam, H. Xu, and S. T. Davidge Arginase contributes to endothelial cell oxidative stress in response to plasma from women with preeclampsia Cardiovasc Res, January 1, 2010; 85(1): 194 - 203. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sankaralingam, H. Xu, Y. Jiang, T. Sawamura, and S. T. Davidge Evidence for Increased Methylglyoxal in the Vasculature of Women With Preeclampsia: Role in Upregulation of LOX-1 and Arginase Hypertension, October 1, 2009; 54(4): 897 - 904. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||