Abstract
The effect of four sulfated polyvinylalcohol–acrylate copolymers and heparin on plasminogen activation and on plasmin activity is studied. The molecules differing in charge (proportion of negatively charged units 40.5%–73.5% of the total) and in size (5600 Da–8800 Da) accelerate plasminogen activation by 2- up to 4-fold at a 7-fold molar excess of the polyvinylacrylates over plasminogen. They, however, exert a concentration and charge-dependent effect on plasmin: both the amidolytic (half-maximal effect at a 1.33–3.66 molar excess of the polyvinylacrylates) and fibrinolytic (half-maximal effect at 1.23–1.72 molar excess of the polyvinylacrylates) activities of plasmin are inhibited. In contrast, heparin (a similarly carboxylated and sulfated polymer) and polyvinylacrylates with a low number of sulfate groups (30% sulfated monomers) at concentrations up to 2.2 μM do not affect plasminogen activation and plasmin activity in a milieu of physiological ionic strength. Experiments with plasmin derivatives lacking N-terminal peptides of different length (des-kringle 1–4 and des-kringle 1–5 plasmin) show identical changes in the protease activities, precluding involvement of the kringle-domain in the interaction with the polyvinylacrylates. Fluorescence studies evidence the charge-dependent binding of the polyvinylacrylates to plasmin, but not to plasminogen. Thus, through non-covalent interaction with the protease-domain of plasmin the polyvinylacrylates inhibit fibrinolysis. Since these sulfated copolymers inhibit both thrombin [4] and plasmin activity, they may be a useful therapeutic tool in situations when both the blood coagulation and the fibrinolytic system are activated (such as intravascular coagulation and fibrinolysis, ICF).
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