title: Sofalcone upregulates the nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 pathway, reduces soluble fms-like tyrosine kinase-1, and quenches endothelial dysfunction: potential therapeutic for preeclampsia.
abstract: Preeclampsia is a severe complication of pregnancy, characterized by hypertension, oxidative stress, and severe endothelial dysfunction. Antiangiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin, play key pathophysiological roles in preeclampsia. Heme oxygenase-1 (HO-1) is a cytoprotective, antioxidant enzyme reported to be downregulated in preeclampsia. Studies propose that inducing HO-1 may also decrease sFlt-1 production. Sofalcone, a gastric antiulcer agent in clinical use, is known to induce HO-1 in gastric epithelium. We aimed to investigate whether sofalcone induces HO-1 and reduces sFlt-1 release from primary human placental and endothelial cells and blocks endothelial dysfunction in vitro. We isolated human trophoblasts and endothelial cells (human umbilical vein endothelial cells) and also used uterine microvascular cells. We investigated the effects of sofalcone on (1) HO-1 production, (2) activation of the nuclear factor (erythroid-derived 2)-like 2 pathway, (3) sFlt-1 and soluble endoglin release, (4) tumor necrosis factor α-induced monocyte adhesion and vascular cell adhesion molecule upregulation, and (5) endothelial tubule formation. Sofalcone potently increased HO-1 mRNA and protein in both primary trophoblasts and human umbilical vein endothelial cells. Furthermore, sofalcone treatment caused nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 and transactivation of other nuclear factor (erythroid-derived 2)-like 2 responsive genes (NQO1, TXN, and GCLC). Importantly, sofalcone significantly decreased the secretion of sFlt-1 from primary human trophoblasts. Sofalcone potently suppressed endothelial dysfunction in 2 in vitro models, blocking tumor necrosis factor α-induced monocyte adhesion and vascular cell adhesion molecule 1 expression in human umbilical vein endothelial cells. These results indicate that in primary human tissues, sofalcone can potently activate antioxidant nuclear factor (erythroid-derived 2)-like 2/HO-1 pathway, decrease sFlt-1 production, and ameliorate endothelial dysfunction. We propose that sofalcone is a novel therapeutic candidate for preeclampsia.
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.).
authors: Kenji
authors: K
authors: Onda
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.).
authors: Stephen
authors: S
authors: Tong
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.).
authors: Anzu
authors: A
authors: Nakahara
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.).
authors: Mei
authors: M
authors: Kondo
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.).
authors: Hideaki
authors: H
authors: Monchusho
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.).
authors: Toshihiko
authors: T
authors: Hirano
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.).
authors: Tu'uhevaha
authors: T
authors: Kaitu'u-Lino
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.).
authors: Sally
authors: S
authors: Beard
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.).
authors: Natalie
authors: N
authors: Binder
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.).
authors: Laura
authors: L
authors: Tuohey
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.).
authors: Fiona
authors: F
authors: Brownfoot
authors: From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (K.O., S.T., T.K.-L., S.B., N.B., L.T., F.B. and N.J.H.); and Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan (K.O., A.N., M.K., H.M., T.H.). nhannan@unimelb.edu.au.
authors: Natalie J
authors: NJ
authors: Hannan
mesh_terms: D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D047188:Chalcones / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D018384:Oxidative Stress; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D011247:Pregnancy; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D047188:Chalcones; D051267:NF-E2-Related Factor 2; C035032:sofalcone; D012313:RNA; D051547:Heme Oxygenase-1; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: heme oxygenase-1; preeclampsia; sFLT-1 protein, human; sofalcone