title: Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia.
abstract: Preeclampsia is a major pregnancy complication where excess placental release of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin causes maternal endothelial and multisystem organ injury. Clinical trials have commenced examining whether pravastatin can be used to treat preeclampsia. However, the preclinical evidence supporting pravastatin as a treatment is limited to animal models, with almost no studies in human tissues. Therefore, we examined whether pravastatin reduced sFlt-1 and soluble endoglin secretion and decreased endothelial dysfunction in primary human tissues. Pravastatin reduced sFlt-1 secretion from primary endothelial cells, purified cytotrophoblast cells, and placental explants obtained from women with preterm preeclampsia. It increased soluble endoglin secretion from endothelial cells but did not change secretion from placental explants. The regulation of sFlt-1 by pravastatin seemed to be mediated via the 3-hydroxy-3-methylglutaryl-coenzyme A reductase cholesterol synthesis pathway. Pravastatin also reduced markers of endothelial dysfunction, including vascular cell adhesion molecule-1 expression and leukocyte adhesion on endothelial cells and increased endothelial cell migration and invasion. We also treated 4 patients with preterm preeclampsia presenting at <30 weeks of gestation with daily pravastatin. Pravastatin seemed to stabilize blood pressure, proteinuria, and serum uric acid levels. Furthermore, serum sFlt-1 levels decreased. We collected the placentas at delivery and found that pravastatin reduced sFlt-1 secretion. These results indicate that pravastatin reduced sFlt-1 and soluble endoglin production and decreased endothelial dysfunction in primary human tissues. We also present pilot data, suggesting that pravastatin can stabilize clinical and biochemical features of preterm preeclampsia. Our data obtained in human tissues support the concept that pravastatin is a candidate therapeutic for preeclampsia.
  
  
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  URL: http://www.anzctr.org.au. Unique identifier: ACTRN12613000268741.
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology (F.C.B., S.T., N.J.H., N.K.B., P.C., R.H., K.O., T.J.K.-L.), Department of Perinatal Medicine (S.P.W.), Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia; and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Japan (K.O.). Fiona.brownfoot@unimelb.edu.au.
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Brownfoot
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology (F.C.B., S.T., N.J.H., N.K.B., P.C., R.H., K.O., T.J.K.-L.), Department of Perinatal Medicine (S.P.W.), Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia; and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Japan (K.O.).
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology (F.C.B., S.T., N.J.H., N.K.B., P.C., R.H., K.O., T.J.K.-L.), Department of Perinatal Medicine (S.P.W.), Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia; and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Japan (K.O.).
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Hannan
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology (F.C.B., S.T., N.J.H., N.K.B., P.C., R.H., K.O., T.J.K.-L.), Department of Perinatal Medicine (S.P.W.), Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia; and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Japan (K.O.).
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Binder
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology (F.C.B., S.T., N.J.H., N.K.B., P.C., R.H., K.O., T.J.K.-L.), Department of Perinatal Medicine (S.P.W.), Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia; and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Japan (K.O.).
authors.forename: Susan P
authors.initials: SP
authors.lastname: Walker
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology (F.C.B., S.T., N.J.H., N.K.B., P.C., R.H., K.O., T.J.K.-L.), Department of Perinatal Medicine (S.P.W.), Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia; and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Japan (K.O.).
authors.forename: Ping
authors.initials: P
authors.lastname: Cannon
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology (F.C.B., S.T., N.J.H., N.K.B., P.C., R.H., K.O., T.J.K.-L.), Department of Perinatal Medicine (S.P.W.), Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia; and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Japan (K.O.).
authors.forename: Roxanne
authors.initials: R
authors.lastname: Hastie
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology (F.C.B., S.T., N.J.H., N.K.B., P.C., R.H., K.O., T.J.K.-L.), Department of Perinatal Medicine (S.P.W.), Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia; and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Japan (K.O.).
authors.forename: Kenji
authors.initials: K
authors.lastname: Onda
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology (F.C.B., S.T., N.J.H., N.K.B., P.C., R.H., K.O., T.J.K.-L.), Department of Perinatal Medicine (S.P.W.), Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia; and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Japan (K.O.).
authors.forename: Tu'uhevaha J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000378:metabolism*; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000378:metabolism; D000071063:Endoglin; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000378:metabolism; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; C064206:ENG protein, human; D000071063:Endoglin; D007136:Immunoglobulins; D011956:Receptors, Cell Surface; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D017035:Pravastatin
keywords: antioxidants; placenta; pravastatin; preeclampsia; pregnancy; trophoblasts