Ahmed, Asif, Rahman, Mahbubur, Zhang, Xian, Acevedo, Carmen H., Nijjar, Sarbjit, Rushton, Ian, Bussolati, Benedetta and St. John, Justin (2000). Induction of placental heme oxygenase-1 is protective against TNFα-induced cytotoxicity and promotes vessel relaxation. Molecular Medicine, 6 (5), pp. 391-409.
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. 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 (TNF) 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 TNF-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. Hemininduced 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.
Divisions: | College of Health & Life Sciences College of Health & Life Sciences > School of Biosciences College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine College of Health & Life Sciences > Aston Medical School |
---|---|
Publication ISSN: | 1528-3658 |
Last Modified: | 25 Nov 2024 08:08 |
Date Deposited: | 21 Mar 2013 11:39 |
Full Text Link: | |
Related URLs: |
http://molmed.o ... articles/18/629
(Publisher URL) |
PURE Output Type: | Article |
Published Date: | 2000-05 |
Authors: |
Ahmed, Asif
(
0000-0002-8755-8546)
Rahman, Mahbubur Zhang, Xian Acevedo, Carmen H. Nijjar, Sarbjit Rushton, Ian Bussolati, Benedetta St. John, Justin |