Statins Prevent the Deleterious Consequences of Placental Chemerin Upregulation in Preeclampsia

Objective: Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin. Design and method: Chemerin levels were determined in a prospective cohort study in women suspected of preeclampsia evaluating the predictive value of the soluble Fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage, and the effects of chemerin in chorionic plate and coronary arteries. Results: Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and pravastatin's fetal/maternal concentration ratio was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate or coronary arteries. In explants, statins upregulated low-density lipoprotein receptor (LDLR) expression, which relies on the same transcription factor as chemerin, and NO release. Conclusions: Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO- and LDLR-dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offer an attractive mechanism by which statins may prevent or treat preeclampsia.