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

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

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.

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