P137	Melatonin is an inhibitor of vascular cell proliferation in vitro.
S.Gendreau, V.Tchaikovski, J.Waltenberger
CARIM, University of Maastricht, Maastricht, NL.

Melatonin is a hormone secreted by the pineal gland, the retina and within the gastrointestinal tract involved in circadian rhythm regulation. An inhibitory effect of Melatonin on prostate cancer cells in vitro and in vivo has been reported. Moreover, Melatonin exerts inhibitory effects on neointimal formation in vivo following PCI in a pig model. Melatonin can also act as a direct free radical scavenger mediating antioxidant actions both in vitro and in vivo. The aim of this project was to identify the effects of Melatonin on human vascular cells and to elucidate the underlying molecular and cellular mechanisms. For this study, we used the following primary vascular cell lines: human coronary artery endothelial cells (HCAEC), human coronary artery smooth muscle cells (HCASMC) and human umbilical vein endothelial cells (HUVEC). Cell proliferation was studied using a MTS-based assay and [3H]thymidine incorporation. Proliferation was induced by stimulation with either VEGF-A for HCAEC and HUVEC or with PDGF-BB for HCASMC. Cytotoxic effects of Melatonin were assessed by LDH (lactate dehydrogenase) release. Migratory responses were tested in the presence and absence of Melatonin by performing growth factor-stimulated chemotaxis experiments using a modified Boyden chamber. Melatonin strongly inhibits the proliferation of HCAEC and HCASMC with an IC50 of about 1.5 mM for HCAEC and 3 mM for HCASMC. Proliferation of HUVEC was also strongly inhibited even at lower concentrations. Melatonin shows no cytotoxic effects. The migratory responses of HCAEC were not impaired by a preincubation of up to 48 hours with Melatonin . This is the first report showing the inhibitory effects of Melatonin on vascular cells. The IC50 values for the inhibition of cellular proliferation speak for a receptor-independent effect of Melatonin, the nature of which is going to be determined. Taken together, these data make Melatonin a good candidate for the prevention of restenosis following PCI.

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