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.
Rajtar
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Giulio Bizzozero Laboratory of Platelet and Leucocyte Pharmacology, Istituto di Ricerche, Farmacologiche Mario Negri, Italy.
Marchi
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de Gaetano
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Cerletti
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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