title: Induction of placental heme oxygenase-1 is protective against TNFalpha-induced cytotoxicity and promotes vessel relaxation.
abstract: BACKGROUND
  Pregnancy is characterized by an inflammatory-like process and this may be exacerbated in preeclampsia. The heme oxygenase (HO) enzymes generate carbon monoxide (CO) that induces blood vessel relaxation and biliverdin that acts as an endogenous antioxidant.
  
  
  METHODS
  We examined the expression and localization of HO-1 and HO-2 in normal and preeclamptic placenta using reverse transcription polymerase chain reaction (RT-PCR), RNase protection assay, immunoblotting and immunohistochemistry. In addition, the effect of HO activation on tumor necrosis factor-alpha (TNFalpha) induced placental damage and on feto-placental circulation was studied.
  
  
  RESULTS
  We provide the first evidence for the role of HO as an endogenous placental factor involved with cytoprotection and placental blood vessel relaxation. HO-1 was significantly higher at term, compared with first trimester placentae indicating its role in placental vascular development and regulation. HO-1 predominantly localized in the extravascular connective tissue that forms the perivascular contractile sheath around the developing blood vessels. HO-2 was localized in the capillaries, as well as the villous stroma, with weak staining of trophoblast. Induction of HO-1 caused a significant attenuation of TNFalpha-mediated cellular damage in placental villous explants, as assessed by lactate dehydrogenase leakage (p < 0.01). HO-1 protein was significantly reduced in placentae from pregnancies complicated with preeclampsia, compared with gestationally matched normal pregnancies. This suggests that the impairment of HO-1 activation may compromise the compensatory mechanism and predispose the placenta to cellular injury and subsequent maternal endothelial cell activation. Isometric contractility studies showed that hemin reduced vascular tension by 61% in U46619-preconstricted placental arteries. Hemin-induced vessel relaxation and CO production was inhibited by HO inhibitor, tin protoporphyrin IX.
  
  
  CONCLUSIONS
  Our findings establish HO-1 as an endogenous system that offers protection against cytotoxic damage in the placenta, identifies the HO-CO pathway to regulate feto-placental circulation and provides a new approach to study the disease of preeclampsia.
authors.affiliation: Department of Reproductive and Vascular Biology, The University of Birmingham, Birmingham Women's Hospital, Edgbaston, UK. A.S.Ahmed@bham.ac.uk
authors.forename: A
authors.initials: A
authors.lastname: Ahmed
authors.forename: M
authors.initials: M
authors.lastname: Rahman
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: C H
authors.initials: CH
authors.lastname: Acevedo
authors.forename: S
authors.initials: S
authors.lastname: Nijjar
authors.forename: I
authors.initials: I
authors.lastname: Rushton
authors.forename: B
authors.initials: B
authors.lastname: Bussolati
authors.forename: J
authors.initials: J
authors.lastname: St John
mesh_terms: D002196:Capillaries / Q000502:physiology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D004790:Enzyme Induction; D005260:Female; D005317:Fetal Growth Retardation / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics*; D051547:Heme Oxygenase-1; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000502:physiology / Q000503:physiopathology; D010920:Placenta / Q000502:physiology* / Q000503:physiopathology; D011225:Pre-Eclampsia / Q000201:enzymology*; D011247:Pregnancy / Q000502:physiology*; D011261:Pregnancy Trimester, First; D011262:Pregnancy Trimester, Second; D011263:Pregnancy Trimester, Third; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D014469:Umbilical Arteries / Q000502:physiology / Q000503:physiopathology
chemical_list: D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2