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Obstetrics & Gynecology 2000;96:582-587
© 2000 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Downregulation of a Mitogen-Activated Protein Kinase Signaling Pathway in the Placentas of Women With Preeclampsia

ALMUT HANNKE-LOHMANN, MD, STEPHANIE PILDNER VON STEINBURG, MD, KERSTIN DEHNE, VALERIE BENARD, PhD, MARTIN KOLBEN, MD, MANFRED SCHMITT, PhD and ERNST LENGYEL, MD

From the Department of Obstetrics and Gynecology, Technische Universität München, Klinikum rechts der Isar, Munich, Germany; and the Department of Immunology and Cell Biology, The Scripps Research Institute, La Jolla, California

Address reprint requests to: Ernst Lengyel, MD Technische Universitat München Department of Obstetrics and Gynecology Klinikum rechts der Isar Ismaninger Str. 22 D-81675 Munich Germany


   Abstract
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Abstract
Material and Methods
 Results
 Discussion
 References
 
Objective: To investigate whether the activity of the three mitogen-activated protein kinases (Jun aminoterminal kinase, extracellular regulated kinase, and p38) is altered in placental tissue of women with preeclampsia and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome.

Methods: Placental activity (measured by immunoprecipitation-kinase assay) and protein expression (measured by western blot) of Jun aminoterminal kinase, extracellular regulated kinase, and p38 mitogen-activated protein kinase were measured in four groups of eight women each with preeclampsia, HELLP syndrome, and normal vaginal or cesarean deliveries. To further characterize the Jun aminoterminal kinase signal transduction pathway, phosphorylation of c-Jun, a downstream effector of Jun aminoterminal kinase– mitogen-activated protein kinase, was analyzed by western blotting, and the activity of Rac1, an upstream activator of the Jun aminoterminal kinase signaling pathway, was determined by pull-down assay.

Results: The activity of Jun aminoterminal kinase was significantly lower in placentas of women with preeclampsia or HELLP syndrome compared with those who had normal vaginal or cesarean delivery, whereas levels of Jun aminoterminal kinase protein expression were similar. Phosphorylation of the transcription factor c-Jun and Rac1 activity also were significantly lower in women with preeclampsia and HELLP than in controls. p38 mitogen-activated protein kinase activity was significantly higher in women with preeclampsia than with HELLP syndrome. There was no change in extracellular regulated kinase activity or protein expression between subgroups.

Conclusion: In placentas of women with preeclampsia or HELLP syndrome, a Rac1-Jun aminoterminal kinase-c-Jun-dependent signal transduction pathway was downregulated.

One important signaling pathway for regulating key cellular functions is the mitogen-activated protein kinase pathway, which consists of at least three parallel protein kinase cascades (Figure 1Go) named after their last kinases, Jun aminoterminal kinase, extracellular regulated kinase, and p38.1,2 Biochemical studies showed that each of the pathways consists of a cascade of three protein kinases, a mitogen-activated protein kinase kinase kinase, a mitogen-activated protein kinase kinase, and a mitogen-activated protein kinase (Figure 1Go). Transmission of signals down the mitogen-activated protein kinase cascade is achieved by sequential phosphorylation and activation of components specific to a respective cascade. Each pathway is activated by a small guanosine triphosphatase, such as Ras or Rac1. For example, the Jun aminoterminal kinase signal transduction pathway is activated by exposing cells to osmotic changes, growth factors, or proinflammatory cytokines,3 leading to activation of the small guanosine trisphosphate-binding protein Rac14 that activates the three-component sequential kinase cascade, the third component of which is Jun aminoterminal kinase–mitogen-activated protein kinase. Activation of Jun aminoterminal kinase results in phosphorylation of the transcription factor c-Jun, increasing its transcriptional activation potential and affecting the expression of various genes.3,5



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  		Figure 1. Cellular signal transduction pathways from membrane receptor to transcription factors in the nucleus by different mitogen-activated protein kinase signal transduction modules. GTPase = guanosine triphosphatase; MAPKKK = mitogen-activated protein kinase kinase kinase; PAK1 = p21-activated kinase-1; MLK = mixed lineage kinase; MEKK1 = mitogen-activated protein kinase kinase kinase-1; HPK1 = hematopoetic progenitor kinase-1; MAPKK = mitogen-activated protein kinase kinase; MEK = mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1; MKK4 = mitogen-activated protein kinase kinase-4; MAPK = mitogen-activated protein kinase; ERK = extracellular regulated kinase; JNK = Jun aminoterminal kinase; MEF2c = myocyte enhancer factor-2c; ATF2 = activated transcription factor-2.

 
The effect of mitogen-activated protein kinases on cellular regulation processes is determined by their activity, so we tested the hypothesis that mitogen-activated protein kinase activity is altered in placentas of women with hypertensive gestational disorders compared with women who have normal pregnancies.


   Material and Methods
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Abstract
 Material and Methods
Results
 Discussion
 References
 
Thirty-two women chosen from a consecutive series who received care at the Department of Obstetrics and Gynecology, Technische Universität München in 1998 were enrolled in this study after giving informed consent. Eight women had severe preeclampsia according to ACOG criteria6 (blood pressure [BP] more than 160/110 mmHg, proteinuria of 3+ in a dipstick random sample or more than 5 g in 24 hours, central nervous system [CNS] symptoms, oliguria). Eight women had symptoms of severe HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome7 defined by platelet count less than 100,000/µL, serum aspartate transferase level higher than 45 U/L, serum lactic dehydrogenase level higher than 600 U/L, right-upper-quadrant abdominal pain, and headaches. Seven of eight women with HELLP had BP above 160/110 mmHg, and four of eight had significant proteinuria. Women with HELLP syndrome were delivered by cesarean according to an institutional guideline, and women with preeclampsia were delivered by cesarean because of severity of disease. Exclusion criteria were multiple pregnancies, multiparity, and other medical conditions such as chronic hypertension, renal disease, autoimmune disorders, or diabetes.

Women with uneventful pregnancies and normal vaginal deliveries (n = 8) or elective cesareans because of breech presentation (n = 8) were chosen as controls. None of the controls had evidence of preeclampsia, HELLP syndrome, pregnancy-induced hypertension, chorioamnionitis, or placental abnormalities that could be detected histologically. Patient characteristics are presented in Table 1Go. Placental samples were collected immediately after delivery, snap frozen in liquid nitrogen, and stored at -80C.


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  		Table 1. Subject Characteristics
 
The mitogen-activated protein kinase assay8 consists of immunoprecipitation of the respective mitogen-activated protein kinase with an antibody and subsequent incubation with a recombinant protein substrate and radioactive adenosine triphosphate. Kinase activity is determined by measuring incorporation of radioactivity into the substrate. In short,9 deep-frozen placental tissue was pulverized, and the resulting powder suspended in a buffer containing Triton X-100 (Roth, Karlsruhe, Germany) and protease inhibitors and cleared by centrifugation. Each experiment was repeated three times for analyses of extracellular regulatedkinase,Junaminoterminalkinase,andp38mitogen-activated protein kinase activity. After normalization for protein (400 µg for each), extracts were incubated with protein A agarose and an antibody (all from Santa Cruz Biotechnology, Santa Cruz, CA) to extracellular regulated kinase (C16), Jun aminoterminal kinase (C17), or p38 (N20), followed by incubation with the specific substrate and [{gamma}-32P] adenosine triphosphate. Substrates for extracellular regulated kinase, Jun aminoterminal kinase, and p38 mitogen-activated protein kinase were myelin basic protein, glutathione S-transferase-c-Jun, and GST-ATF-2, respectively. The beads were removed by centrifugation, and the supernatant was subjected to 15% sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The gel was dried, autoradiographed, and its radioactivity quantified using a Phosphor Imager (Molecular Dynamics, Sunnyvale, CA). For standardization of placental Jun aminoterminal kinase, extracellular regulated kinase, and p38 mitogen-activated protein kinase activity, the cell line NIH3T3 was stimulated by 0.5 M sorbitol (15 minutes), 10 ng/mL epidermal growth factor (30 minutes), and 10 µg/mL anisomycin (30 minutes), respectively. Every gel included a sample from the same cell stimulation. Placental mitogen-activated protein kinase activities are expressed as a percentage of NIH3T3 mitogen-activated protein kinase activity.

Activity of Rac1 was determined by a pull-down assay in which active, guanosine triphosphate-Rac1 was precipitated specifically from placental tissues using the p21-protein–binding domain of p21-activated kinase, a downstream effector of Rac1, and then detected with a Rac1 monoclonal antibody.10 The method was adopted for the first time for the use with tissue. Placental extracts (400 µg) were incubated with 10 µg of glutathione S-transferase protein binding domain and 15 µL of glutathione sepharose 4B beads in binding buffer (25 mM Tris hydrochloride, pH 8.0, 1 mM dithiothreitol, 30 mM magnesium chloride, 40 mM sodium chloride, 0.5% Nonidet P-40) for 1 hour at 4C. The bead pellet was washed three times in binding buffer with 1% Nonidet P-40, two times with the same buffer without Nonidet P-40, and finally resuspended in 4x reducing sample buffer. Guanosine triphosphate-Rac1 bound to the beads and, in parallel, the supernatant containing unbound guanosine diphosphate-Rac1, were resolved by 12.5% sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The proteins were transferred to a nitrocellulose membrane and detected by western blotting with a Rac1 monoclonal antibody (Upstate Biotechnology, Lake Placid, NY). The amount of Rac1 detected was quantified by densitometric scanning.

Western blotting has been described elsewhere.9 C-Jun phosphorylation was detected with a phosphospecific antibody that recognizes only c-Jun phosphorylated at Ser63 (NEB, Beverly, MA). After analyzing c-Jun (Ser63) phosphorylation, the blot was reprobed with an antibody against total c-Jun (NEB, Beverly, MA). To detect extracellular regulated kinase, Jun aminoterminal kinase, and p38 expression, the antibodies C16, C17, and N20 (all from Santa Cruz Biotechnology) were used, respectively. Protein expression was quantified by densitometric scanning.

Statistical significance was calculated with SPSS 8.0 (SPSS Inc., Chicago, IL). To analyze the differences in the overall levels of Jun aminoterminal kinase, extracellular regulated kinase, and p38 mitogen-activated protein kinase; Rac1; and c-Jun in the different groups, a hierarchic multiple comparison procedure was done with the Kruskal-Wallis test. In case of significant differences, pairwise comparisons were done with the Mann-Whitney U test. Results were considered significant at P < .05.


   Results
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Abstract
 Material and Methods
 Results
Discussion
 References
 
There were no significant differences between study groups in maternal age and parity. Birth weight was significantly lower in the preeclampsia and HELLP groups than in the control groups of vaginal and cesarean deliveries. The median birth weight of infants of women with HELLP syndrome was 600 g more than those with preeclampsia, which was at least partially a result of more advanced gestational age at delivery (38.2 versus 35.2 weeks).

Mitogen-activated protein kinase activity but not protein expression is essential for the activation state of the mitogen-activated protein kinase pathway.5 Therefore, we examined Jun aminoterminal kinase, extracellular regulated kinase, and p38 kinase activity. Mitogen-activated protein kinase activity was determined by an immunoprecipitation-kinase assay of placental biopsies taken immediately after vaginal or cesarean deliveries. Jun aminoterminal kinase activity was significantly lower (Figure 2Go, upper panels) in placental tissue from women with preeclampsia compared with control placentas from women who had normal vaginal (P = .001) or cesarean deliveries (P = .006). Jun aminoterminal kinase activity in placentas from women with HELLP syndrome did not differ from those of women with preeclampsia, but it was significantly lower than that of women who had normal vaginal (P = .002) or cesarean deliveries (P = .027). Western blotting with an antibody to Jun aminoterminal kinase showed equal levels of Jun aminoterminal kinase protein in all tissues examined (Figure 2Go, lower panels). Those data suggest that Jun aminoterminal kinase activity, but not protein expression, differed in the groups analyzed. p38 kinase activity was significantly lower in placentas from women with HELLP syndrome compared with those from women with preeclampsia (P = .022), being above and below the median p38 kinase activity in controls (data not shown). However, there was no difference in women with HELLP syndrome or preeclampsia compared with control groups. There was no difference in p38 kinase protein expression between subgroups. The levels of extracellular regulated kinase activity and protein expression were similar for preeclampsia, HELLP syndrome, and controls; no statistically significant difference was found (data not shown).



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  		Figure 2. . Downregulation of Jun aminoterminal kinase (JNK) mitogen-activated protein kinase activity in placental tissue of women with preeclampsia or hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. Activity of JNK mitogen-activated protein kinase in placental tissue of the indicated women was determined with recombinant c-Jun as substrate by an immunoprecipitation kinase assay (upper panels). Radioactivity was quantified with a Phosphor Imager and related to the control of sorbitol-stimulated NIH3T3 cells. Equal expression of JNK protein was verified by immunoblotting (lower panels).

 
To examine whether other members of the Jun aminoterminal kinase signal transduction pathway (Figure 1Go) were downregulated in placental tissue of women with preeclampsia and HELLP syndrome, we investigated an upstream activator of the Jun aminoterminal kinase signal transduction pathway, Rac1,4 and a downstream effector of Jun aminoterminal kinase mitogen-activated protein kinase, the transcription factor c-Jun.3,5 The activity of the transcription factor c-Jun is regulated by phosphorylation, so the phosphorylation status of endogenous c-Jun was examined (Figure 3Go). Consistent with the downregulation of Jun aminoterminal kinase activity in preeclampsia and HELLP syndrome, no phosphorylation of c-Jun was detected in placental tissues of those groups of women, but it could be detected clearly in placentas from women who had normal vaginal and cesarean deliveries (P = .001). Reprobing the blot with an antibody against phosphorylated and unphosphorylated forms of c-Jun showed similar expression of total c-Jun in all samples (data not shown).



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  		Figure 3. Reduced phosphorylation of c-Jun in placental tissues of patients with preeclampsia or hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, determined by immunoblotting with an antibody against phosphorylated c-Jun. Results for cesarean were similar to those for vaginal delivery.

 
Rac1 activity was determined in a pull-down assay10 that measures binding of activated guanosine triphosphate-Rac1 to p21-activated kinase-1 (a downstream effector of Rac1, Figure 1Go), followed by immunoblotting with a Rac1-specific antibody (Figure 4Go). Rac1 in the active guanosine triphosphate state was more abundant in placentas of women who had normal vaginal deliveries and cesareans than in placentas of women with preeclampsia (P = .003) or HELLP syndrome (P = .002). In contrast, detection of nonactive guanosine diphosphate-Rac1 (Figure 4Go) was similar in all placental tissues (Figure 4Go, lower panel).



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  		Figure 4. Reduction of Rac1 activity in placental tissue from women with preeclampsia or hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. Equal amounts of placental tissue extracts of the indicated women were subjected to a pull-down assay using guanosine triphosphate-p21-activated kinase-1/protein-binding domain, which only binds activated guanosine triphosphate-Rac1. The beads (upper panel) containing active guanosine triphosphate-Rac1 and the supernatant (lower panel) containing inactive guanosine diphosphate-Rac1 were subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis and then immunoblotting with a Rac1-specific antibody. Results for cesarean were similar to those for vaginal delivery.

 

   Discussion
Top
Abstract
 Material and Methods
 Results
 Discussion
References
 
Our data indicate that a Rac1-Jun aminoterminal kinase-c-Jun–dependent signal transduction pathway is downregulated in preeclampsia and HELLP syndrome. Delivery mode did not influence mitogen-activated protein kinase activity; none of the three mitogen-activated protein kinase investigated showed differences in protein activity or expression between subgroups of women who delivered vaginally or by cesarean.

Several signaling proteins can link the guanosine triphosphatase Rac1 to Jun aminoterminal kinase and might be part of the respective signaling cascade (Figure 1Go). One candidate effector11 of Rac1 is the serinethreonine kinase p21-activated kinase-1, which can stimulate the Jun aminoterminal kinase signaling pathway12 and becomes activated upon binding of its protein-binding domain to the activated guanosine triphosphate–dependent form of Rac1. Other possible bridges between Rac1 and Jun aminoterminal kinase are the mixed-lineage kinases and mitogen-activated protein kinase kinase kinase-1, which are both able to bind Rac1 and are effective activators of the Jun aminoterminal kinase signaling pathway.11,13,14 The activity and expression levels of those proteins in the placenta are currently unknown, and further studies are necessary to delineate the complete Jun aminoterminal kinase signaling cascade impaired in HELLP and preeclampsia.

A major problem in hypertensive disorders of pregnancy is insufficiency of the uteroplacental circulatory system caused by inappropriate endovascular invasion of trophoblast cells into maternal spiral arteries at 14–20 weeks’ gestation.15,16 That leads to chronic placental hypoxia.17 In a hypoxia model involving rat kidney and heart it was shown that prolonged ischemia leads to downregulation of Jun aminoterminal kinase activity, whereas acute hypoxia leads to upregulation of Jun aminoterminal kinase– mitogen-activated protein kinase activity.18,19 Therefore, one explanation for our finding of reduced Jun aminoterminal kinase activity in placentas of women with preeclampsia or HELLP syndrome could be the chronic hypoxic state of those placentas.

Reports have shown inappropriate expression of certain proteases and their inhibitors in placentas of women with preeclampsia.20 One protease21 that plays an important role in trophoblast invasion is matrix metalloprotease-9, the expression of which is reduced in the placenta during hypertensive gestational disease.20,22 In tumor cell invasion, matrix metalloprotease-9 expression is regulated by a Jun aminoterminal kinase signaling pathway.23 Therefore, our finding that the Jun aminoterminal kinase signaling pathway is downregulated in preeclampsia and HELLP syndrome might explain reduced matrix metalloprotease-9 expression in preeclampsia. Because we measured mitogen-activated protein kinase activity at delivery, which was 20 weeks after the trophoblast invasion was completed, it is unclear whether changes in mitogen-activated protein kinase activity occur in early gestation.

The occurrence of HELLP syndrome can complicate preeclampsia, or it can be an independent clinical entity without hypertension, edema, and proteinuria, the main features of preeclampsia.24 It has been disputed whether preeclampsia and HELLP syndrome have a common pathophysiologic origin or are completely independent types of diseases.7,25 Our results show that both diseases involve impairment of the Jun aminoterminal kinase signal transduction pathway, which points to similarities in pathophysiology. However, p38 mitogen-activated protein kinase activity differs significantly in those diseases, with elevated levels of p38 kinase activity in preeclampsia and lower levels in HELLP syndrome, compared with levels in healthy pregnant women. The obvious differences in p38 kinase activity in preeclampsia and HELLP offer an explanation for the distinct clinical features of the diseases.

In summary, we have shown that the activity of a Rac1-Jun aminoterminal kinase-c-Jun-dependent signal transduction pathway is downregulated in preeclampsia and HELLP syndrome. It is tempting to speculate that downregulation of this signal transduction pathway is involved in impaired activation of genes important for invasion, proliferation, and adhesion of placental cells in preeclampsia and HELLP.


   Footnotes
 
This research was supported by grants from the Technische Universität München (KKF 8756156 to EL and MS) and the Hochschulsonder-programm III zur Förderung von Frauen (AH-L).

The authors thank C. Cramer and U. Berger (Department of Medical Statistics and Epidemiology, Technische Universität München) for help with the statistical analyses.

PII S0029-7844(00)00986-8

Received January 26, 2000. Received in revised form May 23, 2000. Accepted June 15, 2000.


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5. Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 1997;9:180–6.[Medline]

6. American College of Obstetricians and Gynecologists. Hypertension in pregnancy. ACOG technical bulletin no. 219. Washington, DC: American College of Obstetrics and Gynecologists, 1996.

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10. Benard V, Bohl BP, Bokoch GM. Characterization of Rac and Cdc42 activation in chemoattractant-stimulated human neutrophils using a novel assay for active GTPases. J Biol Chem 1999;274:13198–204.[Abstract/Free Full Text]

11. Aspenström P. Effectors of the rho GTPases. Curr Opin Cell Biol 1999;11:96–102.

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19. Laderoute KR, Mendonca HL, Calaoagan JM, Knapp AM, Giaccia AJ, Stork PJ. Mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is induced by low oxygen conditions found in solid tumor microenvironments—A candidate MKP for the inactivation of hypoxia-inducible SAPK/JNK activity. J Biol Chem 1999;274:12890–7.[Abstract/Free Full Text]

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