Heparin prevents programmed cell death in human trophoblast

Article


Hills, F., Abrahams, V., Gonzalez-Timon, B., Francis, J., Cloke, B., Hinkson, L., Rai, R., Regan, L., Mor, G., Sullivan, M., Lam, E. and Brosens, J. 2006. Heparin prevents programmed cell death in human trophoblast. Molecular Human Reproduction. 12 (4), pp. 237-242.
TypeArticle
TitleHeparin prevents programmed cell death in human trophoblast
AuthorsHills, F., Abrahams, V., Gonzalez-Timon, B., Francis, J., Cloke, B., Hinkson, L., Rai, R., Regan, L., Mor, G., Sullivan, M., Lam, E. and Brosens, J.
Abstract

Heparin is used clinically for the prevention of pregnancy complications associated with prothrombotic disorders, especially antiphospholipid antibody syndrome. Recent studies have suggested that heparin may exert direct effects on placental trophoblast, independently of its anticoagulant activity. We now demonstrate that heparin abrogates apoptosis of primary first trimester villous trophoblast in response to treatment with the pro-inflammatory cytokines interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha. This multifunctional glycosaminoglycan also inhibited apoptosis induced by other agents, including staurosporin, broad-spectrum kinase inhibitor and thrombin. Furthermore, heparin attenuated caspase-3 activity, a hallmark of apoptosis, in human first trimester villous and extravillous trophoblast cell lines treated with peptidoglycan, a Toll-like receptor-2 agonist isolated from Staphylococcus aureus. The ability of heparin to antagonize cell death induced by such diverse apoptotic signals suggested that it acts as a survival factor for human trophoblast. We demonstrate that heparin, like epidermal growth factor (EGF) and heparin-binding EGF (HB-EGF), elicits phosphorylation of the EGF receptor and activation of the phosphatidyl inositol 3-kinase (PI3K)-, the extracellular signal-related kinase 1/2 (ERK1/2)- and the c-Jun NH2 terminal kinase (JNK)-signal transduction pathways in primary villous trophoblast. In summary, we have demonstrated that heparin activates multiple anti-apoptotic pathways in human trophoblast. Our results suggest that heparin may be useful in the management of at-risk patients, even in the absence of an identifiable thrombophilic disorder.

Research GroupCentre for Investigative and Diagnostic Oncology
Biomarkers for Cancer group
Reproductive Biology group
PublisherOxford University Press (OUP)
JournalMolecular Human Reproduction
ISSN1360-9947
Publication dates
PrintApr 2006
Publication process dates
Deposited27 Oct 2009
Output statusPublished
LanguageEnglish
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