The antimitogenic action of the sulphated polysaccharide fucoidan differs from heparin in human vascular smooth muscle cells.
The sulphated polysaccharides fucoidan and heparin both inhibit vascular smooth muscle cell (VSMC) proliferation. In this study we compared their actions on mitogenesis and ERK1/ERK2 activation in human VSMC. Although they displaced cell surface [3H]-heparin binding with similar affinity, they exerted clearly distinguishable actions. Fucoidan potently inhibited DNA synthesis stimulated by foetal calf serum, PDGF-BB and thrombospondin-1. Heparin inhibited the mitogenic action of serum and thrombospondin- I (though less potently than fucoidan), but failed to inhibit PDGF-BB-induced DNA synthesis. In parallel studies, fucoidan, but not heparin, inhibited ERK1/ERK2 activation by PDGF-BB. Moreover, fucoidan inhibited serum-induced mitogenesis in "heparin resistant" VSMC, which are refractory to heparin's antimitogenic action. In summary, the structurally different polysaccharides, heparin, fucoidan (and fucans) have distinguishable effects on mitogenesis and ERK1/ERK2 activation, suggesting that different mechanism(s) mediate these actions. The potent antimitogenic action of fucoidan and its efficacy in heparin resistant VSMC emphasise the need to further investigate its mechanism of action in human VSMC and suggest this agent could have therapeutic potential.
Patel
Mahendra K
MK
Clinical Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK. m.k.patel@ic.ac.uk
Mulloy
Barbara
B
Gallagher
Karen L
KL
O'Brien
Leisha
L
Hughes
Alun D
AD
D000818:Animals; D000077214:Becaplermin; D002417:Cattle; D002478:Cells, Cultured / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects; D005312:Fetal Blood / Q000502:physiology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011134:Polysaccharides / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D019700:Thrombospondin 1 / Q000494:pharmacology
D016895:Culture Media, Serum-Free; D006131:Growth Inhibitors; D010982:Platelet-Derived Growth Factor; D011134:Polysaccharides; D020574:Proto-Oncogene Proteins c-sis; D019700:Thrombospondin 1; D000077214:Becaplermin; D006493:Heparin; C007789:fucoidan; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases