Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Herse, F; Lamarca, B; Hubel, CA; Kaartokallio, T; Lokki, AI; Ekholm, E; Laivuori, H; Gauster, M; Huppertz, B; Sugulle, M; Ryan, MJ; Novotny, S; Brewer, J; Park, JK; Kacik, M; Hoyer, J; Verlohren, S; Wallukat, G; Rothe, M; Luft, FC; Muller, DN; Schunck, WH; Staff, AC; Dechend, R.
CYP2J2 Expression and Circulating Epoxyeicosatrienoic Metabolites in Preeclampsia.
Circulation. 2012; 126(25):2990-2999
Doi: 10.1161/CIRCULATIONAHA.112.127340
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- Co-Autor*innen der Med Uni Graz
- Gauster Martin
- Huppertz Berthold
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- Abstract:
- Background-Preeclampsia is a multisystem disorder of pregnancy, originating in the placenta. Cytochrome P450 (CYP)-dependent eicosanoids regulate vascular function, inflammation, and angiogenesis, which are mechanistically important in preeclampsia. Methods and Results-We performed microarray screening of placenta and decidua (maternal placenta) from 25 preeclamptic women and 23 control subjects. The CYP subfamily 2J polypeptide 2 (CYP2J2) was upregulated in preeclamptic placenta and decidua. Reverse-transcription polymerase chain reaction confirmed the upregulation, and immunohistochemistry localized CYP2J2 in trophoblastic villi and deciduas at 12 weeks and term. The CYP2J2 metabolites, 5,6-epoxyeicosatrienoic acid (EET), 14,15-EET, and the corresponding dihydroxyeicosatrienoic acids, were elevated in preeclamptic women compared with controls in the latter two thirds of pregnancy and after delivery. Stimulating a trophoblast-derived cell line with the preeclampsia-associated cytokine tumor necrosis factor-alpha enhanced CYP2J2 gene and protein expression. In 2 independent rat models of preeclampsia, reduced uterine-perfusion rat and the transgenic angiotensin II rat, we observed elevated EET, dihydroxyeicosatrienoic acid, and preeclamptic features that were ameliorated by the CYP epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MsPPOH). Uterine arterial rings of these rats also dilated in response to MsPPOH. Furthermore, 5,6-EET could be metabolized to a thromboxane analog. In a bioassay, 5,6-EET increased the beating rate of neonatal cardiomyocytes. Blocking thromboxane synthesis reversed that finding and also normalized large-conductance calcium-activated potassium channel activity. Conclusions-Our data implicate CYP2J2 in the pathogenesis of preeclampsia and as a potential candidate for the disturbed uteroplacental remodeling, leading to hypertension and endothelial dysfunction. (Circulation. 2012;126:2990-2999.)
- Find related publications in this database (using NLM MeSH Indexing)
- 8,11,14-Eicosatrienoic Acid - analogs & derivatives
- Animals -
- Cells, Cultured -
- Cytochrome P-450 Enzyme System - analysis
- Female -
- Humans -
- Hydrazines - pharmacology
- Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - physiology
- Oligonucleotide Array Sequence Analysis -
- Placenta - blood supply
- Polymorphism, Single Nucleotide -
- Pre-Eclampsia - blood
- Pregnancy -
- Rats -
- Rats, Sprague-Dawley -
- Find related publications in this database (Keywords)
- hypertension
- pregnancy
- preeclampsia
- cytochrome P450