Fedichkina R. The role of L-cysteine different metabolic pathways in cardiac responses to loading

The dissertation is devoted to research of the role of two ways of L-cysteine metabolism in the realization of cardiac function under volume load and reperfusion injury. The inhibitor of cytoplasmic hydrogen sulfide (H2S) synthase propargylglycine (PAG) and the inhibitor of glutathione synthesis buthionine sulfoximine (BSO) were used together with their precursor L-cysteine. Inhibition of H2S synthesis in combination with the addition of L-cysteine has been shown to increase cardiac functional reserves and potent cardioprotective effect. The powerful inotropic effect of the combination of PAG + L-cysteine was abolished by the addition of BSO. This suggests that stimulating endogenous glutathione synthesis is extremely important in heterometric regulation of the heart function. Stimulation of glutathione synthesis from L-cysteine had a potent cardioprotective effect in the model of ischemia-reperfusion of isolated rat heart. Restoration of cardiac function in reperfusion conditions with the addition of PAG + L-cysteine reached 95%, the efficiency of myocardial oxygen consumption was significantly higher than in the control, and all these effects were also reversed by previous administration of BSO. Biochemical studies have shown that in the group pretreated with PAG + L-cysteine significantly reduced the rate of generation of superoxide, hydroxyl radicals and hydrogen peroxide in the heart tissues under ischemia-reperfusion. Decreased levels of malonic dialdehyde and diene conjugates under the action of the combination of PAG + L-cysteine indicate a lower degree of lipid peroxidation induced by ischemia. The content of reduced and oxidized glutathione increased two and a half times in group with PAG + L-cysteine and was significantly higher in reperfusion period. These data suggest that the stimulation of endogenous glutathione synthesis by switching L-cysteine metabolism from hydrogen sulfide formation has a powerful cardioprotective potential. Such activation of antioxidant systems preserved the integrity of mitochondrial membranes and inhibited the formation of mitochondrial permeability transition pores (MPTP), as evidenced by less release of mitochondrial factor into the effluent from isolated rat heart. In addition, post-conditioning with reduced glutathione has been shown to restore isolated heart function, reduce oxygen demand, and prevent MPTP formation during reperfusion, indicating the importance of high glutathione levels during the reperfusion period. Thus, the cardioprotective effect of modulating L-cysteine metabolism has an antioxidant and membrane-stabilizing effects which may be a promising direction for the correction of heart failure and conditions accompanied by reperfusion injury.