Abstract | BACKGROUND: MATERIALS AND 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.
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Authors | A Ahmed, M Rahman, X Zhang, C H Acevedo, S Nijjar, I Rushton, B Bussolati, J St John |
Journal | Molecular medicine (Cambridge, Mass.)
(Mol Med)
Vol. 6
Issue 5
Pg. 391-409
(May 2000)
ISSN: 1076-1551 [Print] England |
PMID | 10952020
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Membrane Proteins
- Tumor Necrosis Factor-alpha
- HMOX1 protein, human
- Heme Oxygenase (Decyclizing)
- Heme Oxygenase-1
- heme oxygenase-2
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Topics |
- Capillaries
(physiology, physiopathology)
- Cell Survival
(drug effects, physiology)
- Enzyme Induction
- Female
- Fetal Growth Retardation
(physiopathology)
- Gene Expression Regulation, Enzymologic
- Heme Oxygenase (Decyclizing)
(biosynthesis, genetics)
- Heme Oxygenase-1
- Humans
- In Vitro Techniques
- Membrane Proteins
- Muscle Contraction
- Muscle, Smooth, Vascular
(physiology, physiopathology)
- Placenta
(physiology, physiopathology)
- Pre-Eclampsia
(enzymology)
- Pregnancy
(physiology)
- Pregnancy Trimester, First
- Pregnancy Trimester, Second
- Pregnancy Trimester, Third
- Reference Values
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Necrosis Factor-alpha
(toxicity)
- Umbilical Arteries
(physiology, physiopathology)
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