Tkachenko V. Oxidative modification of proteins and ways of their prevention in conditions of experimental myocardial ischemia

The dissertation is devoted to the study of non-enzymatic post-translational modifications of proteins (OMP) and identifying ways to prevent the negative effects of these processes under conditions of development of carbonyl-oxidative stress (СOS) in rats with experimental myocardial ischemia. Indicators of OMP, the level of advanced glycation end products (AGEs), AGE-R3 and the activity of proteolytic and antioxidant enzymes in rats with epinephrine-induced myocardial ischemia and pituitrine-isoprenaline-induced myocardial damage (PIMD) were investigated in the work. Exogenous antioxidants, such as quercetin and 2-oxoglutarate; hypoglycemic drug as aminoguanidine and drugs that can affect the processes of degradation of modified proteins as doxycycline and epleranone to assess the possible ways of pharmacological correction of metabolic disorders arising from СOS were used. All tested drugs reduce СOS, by activating the ways of ROS neutralization and dicarbonyl compounds inactivation, by regulating the activity of enzymes of the antioxidant system (the level of SOD in erythrocytes of PIMD- rats almost did not change, activity of catalase in plasma decreased by nearly 5 times, while in contrast, the activity of glutathioneperoxidase in erythrocytes, increased by 1,5 times), and changing in the proteolytic/anti-proteolytic balance (MMP9 activity and α2-macroglobulin level significantly increases in blood, whereas MMP2 activity and α1-proteinase inhibitor level increases in heart) and excretion of OMP products. We established that effects of small doses of doxycycline are comparable to or are greater than the effect of classical antioxidants, such as aminoguanidine and quercetin, and the use of this drug is promising for the treatment of postinfarction heart failure. Investigation of the level of AGE-R3 level, which has AGEs scavenger-receptor properties, of allowed us to establish its ability to the olygomerization and redistribution of AGER-3 forms in experimental myocardial ischemia. We also showed, that antioxidants and doxycycline reduce, the amount of all AGE-R3 forms, except for the tetrameric AGE-R3. This form is significantly increased even in comparison to the PIMD-group. The amount of mono-AGE-R3 decreased tremendously and the level of its oligomeric forms increased after the treatment with Q. In contrast, amount of mono-AGE-R3 forms increased in 5 times and its oligomerization reduced after the treatment with Е. The results of this study this expand understanding of the molecular mechanisms underlying the development of cardiovascular diseases and its complications, and provide important information regarding the ways of their metabolic-based correction.