Experimental Antioxidant Biotherapy for Protection of the Vascular Wall by Modified Forms of Superoxide Dismutase and Catalase

Abstract

The antithrombotic activities of superoxide dismutase and catalase are determined by their effects on reactive oxygen species. Modification of these enzymes with chondroitin sulphate enhances the effect due to accumulation of the derivatives on the surface of the vascular wall cells. We have shown that the effects of covalently modified biocatalysts exceed those of native enzymes, free chondroitin sulphate and their mixtures. The superoxide dismutase-chondroitin sulphate conjugate markedly reduced the thrombus mass, while the catalase-chondroitin sulphate conjugate predominantly preserved blood flow. The magnitude and duration of the antithrombotic activity of modified enzymes in a rat arterial thrombosis model allows one to expect a considerable protective effect after their combined application. A single-bolus intravenous injection of the combination between superoxide dismutase-chondroitin sulphate and catalase-chondroitin sulphate covalent conjugates had a significantly lower antithrombotic effect compared with that of the superoxide dismutase-chondroitin sulphate-catalase bienzymic covalent conjugate. This could be explained by different surface distribution of the conjugates in the circulation after their intravenous administration. Biomedical study of this approach promises a new therapeutic strategy of simple and effective protection of the vascular wall against various injuries with the use of the covalent conjugate superoxide dismutase-chondroitin sulphate-catalase. The review analyses the trends of combined application of enzyme preparations to enhance the effect of antioxidant therapy and to develop conjunctive courses of thrombolytic treatment.

Enzymatic Antioxidants: Next Phase of Pharmacological Effort to Fight Oxidative Stress?

“…Nevertheless, the clinical trial data had not confirmed their universal efficiency established in experimental researches [10,11]. Inconsistency of the clinical results of testing antioxidants was explained by difference of the used models of lesions on animals and cell from the human body environment [1,5], by incorrect choice of the tested antioxidant, parameters of monitoring its activity, amounts of the injected derivative doses, duration of trials, patient selection criteria [9,11].…”

“…Thus, interaction of O 2 ¯ with NO should primary have place in extracellular space [17]. Among all antioxidant enzymes only EC-SOD is localized on the surface of the vascular lumen, interacting with heparan sulphate proteoglycan (and also with collagen [18] and fibulin-5 [19]) by its heparanbinding domain [10,17]. EC-SOD may probably be located along the depth of the whole vascular wall, including the area between endothelium and vessel muscle [20].…”

Translational research into vascular wall function: regulatory effects of systemic and specific factors

“…Formation of antioxidant therapy implies investigation and development of new antioxidant drugs [45,46]. Protective effects of ascorbic acid, trolox, melatonin, polyphenols [47], human recombinant Mn-SOD [48] in hepatic disorders, the effects of chemically modified SOD in lipid oxidation and antioxidant status in diabetic rats [49], changes in SOD and catalase (CAT) activities due to cadmium-induced incorrect folding [50] have been examined.…”

“…Versican is accumulated in the neointima of human blood vessels prone to atherosclerosis [60]. Specific features of chondroitin sulfate [58][59][60] render it into a productive linking agent for antioxidant enzymes [45] and facilitate targeting of the resulting conjugates at the glycocalyx over vascular lesions. This may account for the effectiveness of SOD-CHS-CAT conjugate at small doses [45,46].…”

“…Specific features of chondroitin sulfate [58][59][60] render it into a productive linking agent for antioxidant enzymes [45] and facilitate targeting of the resulting conjugates at the glycocalyx over vascular lesions. This may account for the effectiveness of SOD-CHS-CAT conjugate at small doses [45,46]. It should be noted that in an animal model of endotoxic shock SOD-CHS-CAT significantly increases viability after preventive and therapeutic administration [56].…”