Abstract
We evaluated whether physiological and pre-eclamptic (PE) placentae, characterized by exacerbated inflammation, presented alterations in pro-inflammatory High Mobility Group Box 1 (HMGB1) and its Receptor of Advanced Glycation End products (RAGE) expression. Moreover, we investigated, in physiological placental tissue, the ability of Low Molecular Weight Heparin (LMWH) to modify HMGB1 structural conformation thus inhibiting RAGE binding and HMGB1/RAGE axis inflammatory activity. HMGB1, RAGE, IL-6 and TNFα (HMGB1/RAGE targets) mRNA expression were assessed by Real Time PCR. HMGB1, RAGE protein levels were assessed by western blot assay. Physiological term placental explants were treated by 0.5 U LMWH for 24 or 48 h. HMGB1 and RAGE expression and association were evaluated in LMWH explants by RAGE immunoprecipitation followed by HMGB1 immunoblot. HMGB1 spatial localization was evaluated by immuofluorescent staining (IF). HMGB1 expression was increased in PE relative to physiological placentae while RAGE was unvaried. 24 h LMWH treatment significantly up-regulated HMGB1 expression but inhibited HMGB1/RAGE complex formation in physiological explants. RAGE expression decreased in treated relative to untreated explants at 48 h. IF showed HMGB1 localization in both cytoplasm and nucleus of mesenchymal and endothelial cells but not in the trophoblast. IL-6 and TNFα gene expression were significantly increased at 24 h relative to controls, while they were significantly down-regulated in 48 h vs. 24 h LMWH explants. Our data depicted a new molecular mechanism through which LMWH exerts its anti-inflammatory effect on PE placentae, underlying the importance of HMGB1/RAGE axis in PE inflammatory response.
Highlights
Pre-eclampsia (PE) is a severe placenta-related syndrome that affects 5–8% of all pregnancies, representing one of the main causes of fetal-maternal morbidity and mortality in developed countries [1]
Since pre-eclampsia is characterized by exacerbated placental inflammation, inflammation, we investigated High Mobility Group Box 1 (HMGB1) and Receptor of Advanced Glycation End products (RAGE) expression in PE compared to physiological we investigated HMGB1 and RAGE expression in PE compared to physiological placentae
We found no significant differences in placental HMGB1 expression between PE with Appropriate for Gestational Age (AGA) fetuses
Summary
Pre-eclampsia (PE) is a severe placenta-related syndrome that affects 5–8% of all pregnancies, representing one of the main causes of fetal-maternal morbidity and mortality in developed countries [1]. Molecules 2017, 22, 1997 leading to aberrant placental perfusion, oxidative stress and consequent inflammation and endothelial dysfunction [3,4] This pathologic environment further promotes the release of pro-inflammatory cytokines and syncithiotrophoblast debris into the maternal circulation, directly activating the endothelium causing systemic inflammation [4,5]. Despite intensive investigation on PE pathogenesis, no effective therapy is currently available except for a timed and often pre-term delivery This intervention can resolve maternal symptoms but it could be extremely dangerous for the fetus, causing severe long-term sequelae. Heparin improves pregnancy outcomes with a decrease of placental-mediated complications in women without thrombophilia [25,27]. Our hypothesis is that LMWH inhibition of the placental pro-inflammatory HMGB1/RAGE axis could contribute to the anti-inflammatory activity observed in heparin-treated pre-eclamptic patients. We evaluated placental HMGB1 and RAGE expression in physiological and PE pregnancies and we investigated whether LMWH could modify placental HMGB1 and RAGE expression and/or their binding ability in the human placental tissue
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