Portnychenko A. Molecular mechanisms of cardioprotection in myocardial preconditioning

The study is aimed at estimation of the inductor, signal, mediator and effector mechanisms of delayed cardioprotection, and phenotypic rebuilding in myocardial preconditioning of different genesis. The theoretical concept of induction of preconditioning, the classification of inductors, and criteria for their search have been developed. On this basis, new modes of the preconditioning with acute moderate hypoxia or hyperthermia, and with application of minimal doses of endotoxin have been created. The changes in cardiodynamics, and manifestations of myocardial damage in ischemia-reperfusion of isolated heart after preconditioning in young adult rats, and their age-related changes in mature and old rats have been described. The role of enzymes iNOS, eNOS, COX, and MnSOD, structural protein dystrophin, and caveolin-3 - as mediators; NO, KCa- and KATP-channels, and chaperones HSP70 - as effectors; as well as signal role of kinases Akt and GSK-3? (for signaling and effector phase), and transcription factors HIF-1? and HIF-3? in the development of delayed cardioprotection have been established. The differences of gene and protein expression in the heart ventricles during preconditioning and ischemia - reperfusion, and more powerful cardioprotective mechanisms in the right ventricle have been revealed. The protective inhibitory effects of preconditioning on the function of iNOS, and 5- lipoxygenase during reperfusion have been characterized. We found increase of expression of inhibitory subunit HIF-3?, reduction of dystrophin, reciprocal activation of IGF-1/HSP60/Akt- and GSK-3?-mediated mechanisms in the regression of phenotypic reprogramming (deconditioning), and in hypoxic myocardial remodeling. Among the investigated modes, hypoxic preconditioning has been identified as optimal way of delayed cardioprotection. In the presence of myocardial remodeling, the possible application of hypoxic methods requires determination of risk markers, including the expression level of IGF-1, Akt and dystrophin. Key words: myocardial preconditioning, hypoxia, hyperthermia, cardioprotection, aging, right and left ventricle, mediator and structural proteins, nitric oxide, potassium channels, transcription factors, growth factors, kinases, myocardial remodeling.