Levchenko K. Cardioprotective properties of selective modulators of estrogen receptors in conditions of experimental myocardial infarction

Dissertation is devoted to the study of cardioprotective properties of selective estrogen receptor modulators in conditions of experimental myocardial infarction. It was found in the course of experimental studies that thein vitro modeling of MFP-induced cardiomyocyte hypoxia led to the development of an oxidative stress and a stable energy deficit in the incubation environment. The drugs we studied had auni directional effect with estradiol and were compared by efficiency. The cytoprotective effect of SERM wasalso confirmed by morphological studies.In the modeling of in vitro hypoxia, many mitochondria with irreversible damage were identified, as well as with overload phenomena, that is, with uneven matrix illumination areas, and the crust destruction phenomena. Introducing SERM into the incubation medium led to the improvement of cardiomyocite morphological properties. No damage was observed in the outer membranestructure, there was a large number of high-energy micromitohondrias, while the amount of the mitochondria with crumbled crystals and thematrix illuminationareas was small. Tamoxifen citrate and toremifene appeared to be the most active among the SERM and were selected for the in vivo study. In the in vivo experiments, the biological effects of the SERM under study were unidirectional and had the same effects they had demonstrated in vitro. All of the studied drugs reduced nitrotirosin and homocysteine concentration, and normalized catalase and superoxide dismutase activity. An integrated cytoprotective action also included the SERM ability to regulate the eNOSexpression due to its antioxidant properties, as well as HSP-tropic action. SERM normalized the expressive activity of eNOS by simultaneously restoring the eNOS concentration in the cell. While studying the ST2 concentration in blood plasma of animals with experimental therapy of myocardial infarction, we obtained the following data: SERM, and especially toremipfen, led to a decrease of ST2 in the plasma of experimental animals, which in turn led to an increase of the IL33 and HSP-proteins bioavailability, which is confirmed by the data of many experimental and clinical studies. In this regard, the drugsability to reduce the ST2 concentration, as well as to make a modeling impact on the HSP-proteins, leads to the activation of rapid cellular adaptation processes in hypoxia. The established cardioprotective effects of SERM were demonstrated by their ability to increase the percentage of animals surviving on the 4th day of simulated pathology. Thus, the mechanism of SERM cardioprotective action in acute myocardial infarction is preconditioned by the antioxidant properties that regulate the effect on the ST2 marker and the modulating effect on the expression and synthesis of the endogenous cytoprotection factor of the HSP70-protein. The cardioprotective and cytoprotective effect of selective estrogen receptor modulators was grounded on the basis of experimental studies. It was displayed that their mechanism of action in AMI conditions is based onthe antioxidant properties and modulating effects on the expression and synthesis of endogenous cytoprotection factors such as HSP70-protein and eNOS. The obtained data act as a theoretical basis for the prospective use of this group of drugs as cardioprotectors.