Effects of glycosaminoglycans on platelet and leucocyte function: role of N-sulfation.
The effect of glycosaminoglycans (GAGs) such as sulodexide, low molecular mass dermatan sulfate, heparin and some derivatives with different degrees and types of sulfation was studied on cathepsin G- or thrombin-stimulated platelets and n-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated polymorphonuclear leucocytes (PMNs). All GAGs (0.01-20 micrograms/mL) inhibited both platelet aggregation induced by cathepsin G and its catalytic activity. Thrombin-induced platelet aggregation in contrast was only prevented by heparin, sulodexide and dermatan (2-100 micrograms/mL). All GAGs, except 2-O,N-desulfated heparin, inhibited beta-glucuronidase and lysozyme release, as well as beta-glucuronidase activity and PMN superoxide production by the peptide fMLP. The efficacy of GAGs was clearly dependent on the degree and type of sulfation since dermatan and N-desulfated heparins were comparatively less effective. The observation that heparin and other GAGs inhibit platelet activation induced by the PMN protease cathepsin G may help determine whether mechanisms of action other than anticoagulation are critical in the antithrombotic activity of heparin and related compounds.
Giulio Bizzozero Laboratory of Platelet and Leucocyte Pharmacology, Istituto di Ricerche, Farmacologiche Mario Negri, Italy.
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Cerletti
D001792:Blood Platelets / Q000187:drug effects*; D056649:Cathepsin G; D002403:Cathepsins / Q000494:pharmacology; D003871:Dermatan Sulfate / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D012697:Serine Endopeptidases; D013917:Thrombin / Q000494:pharmacology
D006025:Glycosaminoglycans; D010975:Platelet Aggregation Inhibitors; D003871:Dermatan Sulfate; D009240:N-Formylmethionine Leucyl-Phenylalanine; C007858:glucuronyl glucosamine glycan sulfate; D006493:Heparin; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D013917:Thrombin