title: Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction.
abstract: Preeclampsia is a severe complication of pregnancy. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. Oxidative stress and vascular inflammation exacerbate the endothelial injury. A drug that can block these pathophysiological steps would be an attractive treatment option. Proton pump inhibitors (PPIs) are safe in pregnancy where they are prescribed for gastric reflux. We performed functional studies on primary human tissues and animal models to examine the effects of PPIs on sFlt-1 and soluble endoglin secretion, vessel dilatation, blood pressure, and endothelial dysfunction. PPIs decreased sFlt-1 and soluble endoglin secretion from trophoblast, placental explants from preeclamptic pregnancies, and endothelial cells. They also mitigated tumor necrosis factor-α-induced endothelial dysfunction: PPIs blocked endothelial vascular cell adhesion molecule-1 expression, leukocyte adhesion to endothelium, and disruption of endothelial tube formation. PPIs decreased endothelin-1 secretion and enhanced endothelial cell migration. Interestingly, the PPI esomeprazole vasodilated maternal blood vessels from normal pregnancies and cases of preterm preeclampsia, but its vasodilatory effects were lost when the vessels were denuded of their endothelium. Esomeprazole decreased blood pressure in a transgenic mouse model where human sFlt-1 was overexpressed in placenta. PPIs upregulated endogenous antioxidant defenses and decreased cytokine secretion from placental tissue and endothelial cells. We have found that PPIs decrease sFlt-1 and soluble endoglin secretion and endothelial dysfunction, dilate blood vessels, decrease blood pressure, and have antioxidant and anti-inflammatory properties. They have therapeutic potential for preeclampsia and other diseases where endothelial dysfunction is involved.
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Kenji
authors.initials: K
authors.lastname: Onda
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.). stong@unimelb.edu.au.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Sally
authors.initials: S
authors.lastname: Beard
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Natalie
authors.initials: N
authors.lastname: Binder
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Masanaga
authors.initials: M
authors.lastname: Muto
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Sevvandi N
authors.initials: SN
authors.lastname: Senadheera
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Laura
authors.initials: L
authors.lastname: Parry
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Mark
authors.initials: M
authors.lastname: Dilworth
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Lewis
authors.initials: L
authors.lastname: Renshall
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Fiona
authors.initials: F
authors.lastname: Brownfoot
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Roxanne
authors.initials: R
authors.lastname: Hastie
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Laura
authors.initials: L
authors.lastname: Tuohey
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Kirsten
authors.initials: K
authors.lastname: Palmer
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hirano
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Tu'uhevaha
authors.initials: T
authors.lastname: Kaitu'u-Lino
authors.affiliation: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., S.B., N.B., F.B., R.H., L.T., K.P., T.K.-L., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan (K.O., T.H.); Research Institute for Microbial Diseases, Osaka University, Japan (M.M., M.I.); School of Biosciences, University of Melbourne, Parkville, Victoria, Australia (S.N.S., L.P.); Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, United Kingdom (M.D., L.R.); St Mary's Hospital, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, United Kingdom (M.D., L.R.).
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Hannan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000071063:Endoglin / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D018384:Oxidative Stress; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics*; D014664:Vasodilation
chemical_list: D000071063:Endoglin; D054328:Proton Pump Inhibitors; D012333:RNA, Messenger; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: hypertension; preeclampsia; pregnancy; proton pump inhibitors; therapeutics