THE STUDY OF MECHANISMS OF THE ACTION OF METILIN IN MYOCARDIAL ISCHEMIA/REPERFUSION INJURY

DOI: https://doi.org/10.29296/24999490-2018-02-06

O.I. Pisarenko, V.S. Shulzhenko, I.M. Studneva, Yu.A. Pelogeykina, O.M. Veselova National Medical Research Center of Cardiology, 3rd Cherepkovskaya, 15A, Moscow, 121552, Russian Federation E-mail: [email protected]

The aim of the study. This study was designed to explore relationships between the activation of signaling pathways triggered by a novel cardioprotective drug Metilin, on one hand, and the recovery of metabolic state and the membrane stability in cardiomyocytes, on the other hand. Methods. Metilin was synthesized by the automatic solid phase method using Fmoc technology and identified by 1H-NMR spectroscopy and mass spectrometry. Isolated perfused working rat hearts subjected to global ischemia and reperfusion were used. Results. The administration of mitogen-activated protein kinase (MEK1/2), phosphoinositide 3-kinase (PI3K) or NO-synthase (NOS) inhibitors profoundly reduced the impact of cardioprotection with Metilin, namely decreased metabolic and functional recovery of reperfused hearts and enhanced sarcolemma permeability. Abolishing the cardiac function recovery was accompanied by the deterioration of the myocardial metabolic state and an increase in the damage of cardiomyocyte membrane when coadministration of Metilin with phospholipase C inhibitor (PLC) or sarcolemmal Na+/H+ exchange blocker was applied. Tight correlations were found between the functional and metabolic recovery of reperfused hearts in the studied groups. Conclusion. The obtained results demonstrate that mechanisms of enhanced metaboliс recovery and membrane stability induced by Metilin in ischemic heart involve signaling via PLC and survival kinases, PI3K, and MEK1/2, with activation of downstream targets, NOS and the sarcolemmal Na+/H+ -exchanger.
Keywords: 
metilin, signal transduction, cardioprotection, ischemia, reperfusion
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