By Nikki Withers, medwireNews Reporter
Study findings suggest that uteroplacental cytochrome P450 (CYP) subfamily 2J polypeptide 2 (CYP2J2) overexpression contributes to preeclampsia.
Previous studies have shown that CYP-dependent eicosanoids regulate vascular function, inflammation, and angiogenesis, all of which are mechanistically important in preeclampsia, explain Florian Herse (Experimental and Clinical Research Centre, Berlin, Germany) and colleagues.
They therefore investigated associations between human preeclampsia and CYP epoxygenases.
Placental, fat, and muscle biopsies were obtained following cesarean sections from 25 preeclamptic women and 23 women with normotensive and uncomplicated pregnancies.
Microarray screening of preeclamptic decidual tissue and preeclamptic placenta found that, of 58 CYP genes, only CYP2J2 was significantly upregulated in both tissues (3.90- and 1.55-fold, respectively).
The CYP2J2 protein was specifically localized to the trophoblasts in these uteroplacental tissues, writes the research team in Circulation, and TNFα in trophoblasts was identified as a key stimulator of CYP2J2.
Further analysis showed that the development of preeclampsia was associated with increased circulating levels of CYP2J2 and, in particular, of 5,6-epoxyeicosatrienoic (EET) and dihydroxyeicosatrienoic (DHET) acids, even before clinical onset of the syndrome.
The researchers then performed experiments in a transgenic preeclamptic rat model which featured hypertension and albuminuria from day 13 of pregnancy and beyond. They found that 5,6-EET and 5,6-DHET levels were significantly elevated compared with normal pregnant rats, whereas other metabolites were not significantly dysregulated.
Furthermore, pharmacologic inhibition of CYP epoxygenases or cyclooxygenase reduced hypertension and increased pup weight. This, say the researchers, indicates that enhanced EET biosynthesis may play a detrimental role in the development of preeclampsia.
"Most of these novel findings may come as a surprise, when compared to previous studies demonstrating exclusively beneficial roles of EETs in the regulation of cardiovascular and renal function," say Herse et al. "Future studies should elucidate which CYP2J2-dependent metabolites gain access to the maternal systemic circulation."
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