Dissertation: 137 p., 2 tables, 29 figures, 136 references.
Keywords: heart, insulin resistance, metabolic syndrome, high-fat diet, hypoxia, preconditioning, ischemia, reperfusion, cardioprotection, mitochondria, mitochondrial dysfunction, oxidative stress, morphological changes, PGC-1α, rats.
The dissertation is devoted to establishing mitochondrial mechanisms of cardioprotection in rats with insulin resistance and the influence of hypoxic preconditioning.
The following methods were used in the study: modeling of insulin resistance, hypoxic preconditioning, ischemia-reperfusion of the isolated heart according to the Langendorff method, study of the function of isolated mitochondria by the Chance polarographic method, insulin tolerance test, study of carbohydrate and lipid metabolism, activity of pro- and antioxidant enzymes, determination of the size of myocardial infarction, electron microscopy and immunoblotting.
New information was established about mitochondrial compensatory mechanisms in insulin resistance, which contribute to the restoration of carbohydrate and lipid metabolism in the myocardium, strengthening the mitochondrial apparatus of the heart and energy provision of its function, which limits the development of oxidative stress and ischemic-reperfusion injury to the myocardium. It was first established that the development of insulin resistance after a high-fat diet for 2 weeks is accompanied by a restructuring of the oxidation of energy substrates in mitochondria towards a deterioration in the oxidation of glutamate and succinate, while palmitoyl oxidation showed a tendency to increase. Cardioprotective manifestations of activation of mitochondrial mechanisms in insulin-resistant myocardium were characterized for the first time, namely, postischemic improvement of cardiac contractile function, limitation of manifestations of oxidative stress, mitochondrial damage and manifestations of their dysfunction.
New information was established about the mechanisms of development of myocardial preconditioning under conditions of insulin resistance, namely, the involvement of PGC-1α–dependent mitochondrial mechanisms in the structural protection of the myocardium and the loss of functional protection due to the limitation of mitochondrial energy metabolism. It was first established that the activation of PGC-1α-mediated compensatory mechanisms, namely, stimulation of mitochondrial biogenesis, the transition of mitochondria to the use of other energy substrates, and the limitation of oxidative stress, was ensured in insulin resistance and the influence of hypoxia by an increase in the expression of this protein in the myocardium, which prevailed in the right ventricle of the heart, as well as by an increase in the content of the PGC-1α activator of high-density lipoproteins in peripheral blood.
The dissertation is of fundamental and practical importance. The results of the work can be used in clinical medicine to clarify recommendations for the use of preconditioning methods and hypoxia therapy in patients with metabolic disorders, as well as in scientific and educational institutions of the medical profile.
