Heme Oxygenase-1 Is Not Decreased in Preeclamptic Placenta and Does Not Negatively Regulate Placental Soluble fms-Like Tyrosine Kinase-1 or Soluble Endoglin Secretion.
Elevated placental release of the antiangiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG), is central to the pathophysiology of preeclampsia. It is widely accepted that heme oxygenase-1 (HO-1) is decreased in preeclamptic placenta and negatively regulates sFlt-1 and sENG production. We set out to verify these contentions. There was no difference in HO-1 mRNA or protein levels in preterm preeclamptic placentas (n=17) compared with gestationally matched controls (n=27). In silico analysis of microarray studies did not identify decreased placental HO-1 expression in preeclamptic placenta. Silencing HO-1 in primary trophoblasts did not affect sFlt-1 protein secretion after 24 or 48 hours. Silencing nuclear factor (erythroid-derived 2)-like 2 (transcription factor that upregulates HO-1) in trophoblasts also did not affect sFlt-1 secretion. Administering tin protoporphyrin IX dichloride (HO-1 inhibitor) or cobalt protoporphyrin (HO-1 inducer) into placental explants did not affect sFlt-1 or sENG secretion. Silencing HO-1 in 2 types of primary endothelial cells (human umbilical vein endothelial and uterine microvascular endothelial cells) significantly increased sFlt-1 secretion but not sENG secretion. However, HO-1 silencing selectively increased mRNA expression of sFlt-1 i13 (generically expressed sFlt-1 variant) but not of sFlt-1 e15a (sFlt-1 variant mainly expressed in placenta). Furthermore, adding tin protoporphyrin IX dichloride decreased sFlt-1, whereas adding HO-1 inducers (cobalt protoporphyrin, dimethyl fumarate, and rosiglitazone) either had no effect or increased sFlt-1 or sENG secretion (these trends are opposite to what is expected). We conclude that HO-1 expression is not decreased in preeclamptic placenta and HO-1 does not negatively regulate placental sFlt-1 and sENG secretion in placental or endothelial cells.
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.). stong@unimelb.edu.au.
Stephen
S
Tong
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.).
Tu'uhevaha J
TJ
Kaitu'u-Lino
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.).
Kenji
K
Onda
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.).
Sally
S
Beard
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.).
Roxanne
R
Hastie
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.).
Natalie K
NK
Binder
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.).
Cathy
C
Cluver
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.).
Laura
L
Tuohey
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.).
Clare
C
Whitehead
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.).
Fiona
F
Brownfoot
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.).
Manarangi
M
De Silva
From the Translational Obstetrics Group, the Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia (S.T., T.J.K.-L., K.O., S.B., R.H., N.K.B., C.C., L.T., C.W., F.B., M.D.S., N.J.H.); Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Tokyo, Japan (K.O.); and Department of Obstetrics and Gynaecology, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South Africa (C.C.).
Natalie J
NJ
Hannan
D015703:Antigens, CD / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D000071063:Endoglin; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051547:Heme Oxygenase-1; D040281:Vascular Endothelial Growth Factor Receptor-1
FLT1 protein, human; heme oxygenase-1; placenta; preeclampsia; pregnancy