HEPARIN AND ITS DERIVATIVES MODULATE SERINE PROTEINASES (SERPS) SERINE PROTEINASE-INHIBITORS (SERPINS) BALANCE - PHYSIOPATHOLOGICAL RELEVANCE

Heparin and heparan sulfate, exhibiting wide biological interactions, are constituted of block structures. A defined pentasaccharide motif w as found responsible for the enhancement of the rate of inactivation o f factor Xa by antithrombin III. Heparan also interacts with other ser ine proteinase inhibitors as protease nexin I, and thus possibly modul ates extracellular matrix proteolysis by serine proteinases in the per icellular environment. Human neutrophil elastase (HNE) activity is inh ibited by heparin with K-i = 75 pM. This strong interaction is electro static, involving HNE/arginine residues disposed in a ''cluster shoe'' arrangement on the surface of the molecule and mainly OSO3- groups of heparin. HNE-heparin interactions also interfere with HNE association s with its natural inhibitors: it decreases the rate of association of HNE with alpha(1) proteinase inhibitor (alpha(1)P(i)) by 3 orders of magnitude, while increasing k(ass) between HNE and mucus bronchial inh ibitor (MBI) by > 10 fold. In vivo experiments demonstrated that hepar in fragments lacking anticoagulant activity were able to nearly comple tely abolish emphysematous lesions induced in mice by a single intratr acheal administration of 200 mu g HNE. Long chain unsaturated fatty ac ids peptide conjugates were described as competitive HNE inhibitors (H ornebeck W. et al. 1985). We synthesized N-oleoyl heparin derivative ( 3 oleoyl groups/one molecule of heparin); such a lipophilic glycosamin o-glycan (LipoGAG), although acting as an elastin protecting agent, po ssessed lower HNE inhibitory capacity as compared with heparin. In con trast, however, it was able to inhibit other serine proteinases such a s urokinase, plasmin, porcine pancreatic alpha-chymotrypsin and elasta se. Such Lipo GAG's can be therefore useful to control matrix metallop roteinases (MMPs) during tissue remodeling or tumor invasion.