Lapikova-Bryhinska T. The role of insulin-like growth factor 1 (IGF1) in the molecular and genetic mechanisms of myocardial hypertrophy

The dissertation is devoted to the study of the role of IGF1 in mechanisms of development of cardiac hypertrophy: urgent, isoproterenol-induced, and permanent in spontaneously hypertensive rats. The function and structure of the heart, as well as changes that occurred at the molecular genetic level, were studied. For the first time, the development and reverse dynamics of emergency hypertrophy in Wistar and SHR rats and associated changes in the expression of target genes and proteins involved in the functioning of the cardiovascular system were characterized. The manifestations and mechanism of development of left ventricular hypertrophy in the dynamics of development of urgent and permanent hypertrophy caused by the influence of adrenergic stimuli and post-load in spontaneous arterial hypertension are investigated. For the first time, the dynamics and microRNA-1-mediated regulation of one of the key regulators of cardiac hypertrophy - IGF1 in the process of acute and chronic development of hypertrophy - were characterized. Impaired maturation and decreased expression of microRNA-1, which developed with age and was more pronounced in SHR, were observed, as a result of which the levels of IGF-1 protein in the myocardium increased regardless of the presence of hypertrophy. Intraventricular measurement of pressure and volume with a microcatheter Millar instruments showed that the development of persistent hypertrophy in SHR was accompanied by a decrease of pumping and systolic function of the heart, but the effect of isoproterenol to a lesser extent impaired heart function than in Wistar rats, and even pump and diastolic function improvement. Acute isoproterenol-induced myocardial hypertrophy progressively developed within 7 days of exposure to the adrenergic stimulus and was reversed after fourteen days. In the presence of chronic hypertrophy, the hypertrophic stimulus caused significant mortality, and the reverse development of hypertrophic myocardial rearrangement did not occur. It was also found that Increased levels of hypertrophy in all experimental groups, accompanied by increased arterial stiffness and fibrotic changes in the myocardium, also showed changes in the expression of the following proteins: dystrophin, Akt, SERCA2, IGF-1 protein, and HSP60 cofactor, as well as changes in IGF-1 gene and microRNA1 expression. It was shown for the first time that the long-term development of myocardial hypertrophy in hypertension in 18-month-old rats was characterized by an increase in morphological manifestations of myocardial remodeling and progressive decline of pumping, systolic and diastolic heart function compared to both 6-month-old SHR and Wistar rats. Based on the obtained results, long-term chronic hypertrophy in SHR can be considered as a model of heart failure.