Antioxidant enzymes as potential targets in cardioprotection and treatment of cardiovascular diseases. Enzyme antioxidants: the next stage of pharmacological counterwork to the oxidative stress

Abstract

The focus in antioxidant research is on enzyme derivative investigations. Extracellular superoxide dismutase (EC-SOD) is of particular interest, as it demonstrates in vivo the protective action against development of atherosclerosis, hypertension, heart failure, diabetes mellitus. The reliable association of coronary artery disease with decreased level of heparin-released EC-SOD was established in clinical research. To create a base for and to develop antioxidant therapy, various SOD isozymes, catalase (CAT), methods of gene therapy, and combined applications of enzymes are used. Covalent bienzyme SOD-CHS-CAT conjugate (CHS, chondroitin sulphate) showed high efficacy and safety as the drug candidate. There is an evident trend to use the components of glycocalyx and extra-cellular matrix for target delivery of medical substances. Development of new enzyme antioxidants for therapeutic application is closely connected with progress in medical biotechnology, the pharmaceutical industry, and the bioeconomy.

Keywords: antioxidant therapy.; cardiovascular diseases; catalase; endothelial glycocalyx; enzyme antioxidants; extracellular superoxide dismutase; novel bienzyme superoxide dismutase - chondroitin sulphate - catalase conjugate; oxidative stress; reactive oxygen species; vascular wall injury.

Figure 1

Antithrombotic effects of various combinations of superoxide dismutase (SOD) and catalase (CAT) derivatives and SOD-CHS-CAT conjugate on (A) occlusion time and (B) formed thrombus mass in rat model of arterial thrombosis (intervals of effects are shown as dark areas at the top of bars). 1, control; 2, SOD + CAT; 3, SOD + CHS + CAT; 4, SOD + (CAT-CHS); 5, (SOD-CHS) + CAT; 6, (SOD-CHS) + (CAT-CHS); 7, SOD-CHS-CAT conjugate. Each combination was injected at the same dose of SOD (37±3 U) and CAT (80±3 U) activity as the SOD-CHS-CAT conjugate. Each group of animals consisted of 6 rats. Error values of the specific activity determination did not exceed 2–4%.

Figure 2

The influence of bienzyme SOD-CHS-CAT conjugate in rat model of arterial thrombosis (A) on occlusion time and (B) on obtained thrombus mass. Control rats (with the same arterial injury) were injected normal saline instead of the bienzyme conjugate. The control values were assume to be 100%. Reverse magnitude of the thrombus mass was used to provide a better demonstration (B). The SOD-CHS-CAT doses are given as units of enzyme activity injected per rat.