The combination of modified antioxidant enzymes for anti-thrombotic protection of the vascular wall: the significance of covalent connection of superoxide dismutase and catalase activities.
Vascular wall protection can be achieved by preventive attachment to the vascular wall of antioxidants and elimination/neutralization of toxic products after their disproportioning. For this purpose we have prepared covalent conjugates between the vascular wall glycosaminglycan chondroitin sulfate (CHS) and the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). The following conjugates were obtained: SOD-CHS, CAT-CHS and SOD-CHS-CAT. Their anti-thrombotic activity was compared in a rat model of arterial thrombosis by measuring the time of occlusion emergence and thrombus mass. It is noteworthy that the effectiveness of single bolus injections of SOD-CHS/CAT-CHS mixture was much lower than that of the bienzymic SOD-CHS-CAT conjugate. The conjugate SOD-CHS-CAT proved to be anti-thrombotically effective in doses two orders of magnitude lower than the native biocatalysts and an order of magnitude lower than SOD-CHS and CAT-CHS derivatives. For effective anti-thrombotic protection in oxidative conditions it is important to maintain the stable connection of SOD and CAT activity on the vascular wall and the large size of these conjugates. Covalent conjugate SOD-CHS-CAT is the best prospect for pharmaceutical development.
Maksimenko
Alexander V
AV
Institute of Experimental Cardiology, Russian Cardiology Research-and-Production Complex, 3-rd Cherepkovskaya Street 15a, 121552 Moscow, Russia. alexmak@cardio.ru
Golubykh
Vladimir L
VL
Tischenko
Elena G
EG
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002374:Catalase / Q000494:pharmacology*; D002712:Chlorides; D002809:Chondroitin Sulfates / Q000737:chemistry; D004195:Disease Models, Animal; D005290:Ferric Compounds / Q000008:administration & dosage / Q000633:toxicity; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000494:pharmacology*; D013927:Thrombosis / Q000503:physiopathology / Q000517:prevention & control*
D000975:Antioxidants; D002712:Chlorides; D005290:Ferric Compounds; D002809:Chondroitin Sulfates; D002374:Catalase; D013482:Superoxide Dismutase; C024555:ferric chloride