Mol. Hum. Reprod. Advance Access published online on March 23, 2006
Molecular Human Reproduction, doi:10.1093/molehr/gal026
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1 Institute of Reproductive and Developmental Biology, Wolfson & Weston Research Centre for Family Health, Imperial College London, Hammersmith Hospital, London, UK; Biomedical Sciences, Institute of Health and Social Research, School of Health and Social Sciences, Middlesex University, London, UK
* To whom correspondence should be addressed. 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)-
Received December 16, 2005
Revised February 8, 2006
Accepted February 12, 2006
Article
Heparin prevents programmed cell death in human trophoblast
Frank A.Hills 1,
Vikki M.Abrahams 2,
Belen González-Timón 3,
Julia Francis 4,
Brianna Cloke 4,
Larry Hinkson 4,
Raj Rai 5,
Gil Mor 2,
Lesley Regan 5,
Mark Sullivan 4,
Eric W.-F.Lam 3,
and
Jan J.Brosens 4 *
2 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
3 Cancer Research-UK Labs, Department of Oncology, Imperial College London, Hammersmith Hospital, London
4 Institute of Reproductive and Developmental Biology, Wolfson & Weston Research Centre for Family Health, Imperial College London, Hammersmith Hospital, London, UK
5 Clinical Department of Obstetrics and Gynaecology, Imperial College London, St Mary’s Hospital, London
Jan J.Brosens, E-mail: j.brosens{at}imperial.ac.uk
Abstract 
and tumour necrosis factor (TNF)-
. 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.
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