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.