Tag Archives: SU 11654

Preeclampsia (PE) affects 5-8% of pregnancies and is responsible for 18%

Preeclampsia (PE) affects 5-8% of pregnancies and is responsible for 18% of maternal deaths in the US and for long-term complications in mother and child. the placenta. Consistent with previous studies an increase in inflammation hypoxia and apoptotic cell death was observed in PE compared to normotensive pregnancies. Levels Rabbit Polyclonal to OR4A15. of TNFα IL-6 and IL-8 and HIF-1α were significantly greater whereas the angiogenic marker VEGF was significantly reduced in MPE vs. FPE. Sexual dimorphism was also observed in the activation of cell death: the number of TUNEL-positive cells and the expression pro-apoptotic markers PUMA and Bax being higher in MPE vs. FPE. We also found an increase in the levels of protein and DNA-binding activity of NFκB p65 in MPE vs. FPE. In summary we show here that in preeclamptic pregnancies the placentas of males were associated with significantly higher expression of inflammatory hypoxia and apoptotic molecules but reduced expression of a pro-angiogenic marker compared to placentas of female fetuses. We propose that the transcription factor NFκBp65 might at least partially be involved in sexual dimorphism during PE. studies on placental explants and trophoblasts have shown that hypoxia can activate a sequence of events starting with upregulation of HIF-1α and eventually lead to apoptotic cell death (19). Since we observed apoptosis in preeclamptic placentas we suggest that it can be caused by relative hypoxia during preeclampsia. There is a growing body of evidence however suggesting that HIF-1α can also be activated through inflammation-related factors that include cytokines (IL-1β and TNFα) with NFκB as key link that drives cytokine cellular signaling (38). Studies have demonstrated the ability of NFκB to upregulate expression of HIF-1α under normoxic conditions (39). There is a crosstalk between hypoxia and inflammation in placenta: it was reported that HIF-1α activates NFκB that NFκB controls HIF-1α transcription and that HIF-1α activation may be concurrent with inhibition of NFκB (39). NFκB is a redox-sensitive transcription factor regulating a battery of inflammatory genes and has a variety of different effects in numerous pathological states (40). Activation of NFκB binding and increased caspase-3 both affects the endothelial cells under hypoxic conditions (41). In most cells NFκB is found in the cytoplasm in its inactive SU 11654 form bound to inhibitory proteins. Many extracellular stimuli including SU 11654 bacterial lipopolysaccharide viruses oxidants inflammatory cytokines and immune stimuli can activate NFκB. Once activated it binds to regulatory DNA elements in the promoter regions of inflammatory and immune response genes such as those encoding pro-inflammatory cytokines chemokines enzymes relevant for inflammation and adhesion molecules (41). Aban et SU 11654 al. have reported SU 11654 elevated NFκB immunostaining in placentas complicated by growth restriction and preeclampsia along with apoptotic markers (42). Vaughan and Walsh have shown a marked increase in NFκB activity in preeclamptic placentas as well as in cultured trophoblasts exposed to either hypoxia or inflammation or both (43). We also found an increase in NFκB activity in preeclamptic placentas vs. normotensive placentas. In addition to this we show that expression and activation of NFκB were changed in fetal-sex dependent manner. In conclusion for the first time we report sexual dimorphism in pro-inflammatory cytokine production and apoptosis in the placenta in the setting of preeclampsia. We also found an increase in the expression and DNA binding activity of NFκB p65 in the preeclamptic placentas SU 11654 compared to normotensive placentas with much higher levels in placentas of males compared to females. We propose that increased inflammation and trophoblast cell death observed in the placenta of preeclamptic pregnancies are at least partially induced by NFκB p65 further emphasizing the role of inflammation in the etiology of preeclampsia. We hypothesize that the sex differences in the placental inflammatory response and subsequent pathological changes might affect these fetuses as they reach adulthood. It was suggested by Nicolette et al. (44) that inflammation might compromise the development of the fetal innate immune response supporting hypothesis of origins of neonatal and.