Protective Effects of Meldonium in Experimental Models of Cardiovascular Complications with a Potential Application in COVID-19

Figures

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  Figure 1. Effects of meldonium administration on the (A) end-diastolic area (EDA) of the right ventricle, (B) end-systolic area (ESA) of the right ventricle and (C) fractional area change of the right ventricle (RVFAC). Treatment with meldonium significantly decreased ESA and increased RVFAC compared with the monocrotaline (MCT) group. The data are shown as the mean ± SEM of 7 to 10 animals. * p < 0.05 vs. the MCT group, one-way ANOVA with Dunnett’s multiple comparison test.

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  Figure 2. The effects of meldonium treatment (200 mg/kg for 4 weeks) on the mitochondrial respiration rate (A) and flux control factors (B) in right ventricular (RV) cardiac fibers 4 weeks after monocrotaline (MCT) injection. MCT administration induced inhibition of fatty acid (FA)-dependent oxidative phosphorylation, stimulation of pyruvate metabolism and partial complex I dysfunction. Treatment with meldonium restored mitochondrial functionality in the heart. The results are presented as the mean ± SEM of 9 to 12 animals. * p < 0.05 vs. the MCT group, one-way ANOVA with Dunnett’s multiple comparison test. Flux control factor, the contribution of each substrate/pathway to the respiration rate; S, succinate; F, FA oxidation-dependent pathway; N, NADH pathway; LEAK, substrate-dependent state; OXPHOS, oxidative phosphorylation-dependent state; ROX, residual oxygen consumption.

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  Figure 3. The effects of meldonium treatment (200 mg/kg for 4 weeks) on mitochondrial function/reactive oxygen species (ROS) production after in vitro anoxia-reoxygenation in left ventricular (LV) cardiac fibers in a model of pulmonary hypertension-induced right ventricle heart failure. Anoxia-reoxygenation induced a significantly higher H2O2 production rate and H2O2/O ratio in the monocrotaline (MCT) group than in the control group. Treatment with meldonium decreased anoxia-reoxygenation-induced H2O2 production to the level of the control group. The data are shown as the mean±SEM of 9 to12 experiments. * p < 0.05 vs. MCT group, one-way ANOVA with Dunnett’s multiple comparisons test.

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  Figure 4. Effects of meldonium pretreatment on the lipopolysaccharide (LPS)-induced decrease in (A) ejection fraction and (B) fractional shortening. Pretreatment with meldonium significantly attenuated the development of the inflammation-induced decrease in the ejection fraction and fractional shortening of the left ventricle. The results are shown as the mean±SEM of 7 to 8 animals. * p < 0.05 vs. the LPS group, one-way ANOVA followed by Dunnett’s multiple comparison test.

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  Figure 5. Mitochondrial respiration rate (A) and flux control factors (B) in cardiac fibers of the left ventricle after administration of meldonium at a dose of 100 mg/kg for 3 weeks in a model of lipopolysaccharide (LPS)-induced left ventricle dysfunction. LPS induced the inhibition of fatty acid (FA)-dependent oxidative phosphorylation (A,B) and subsequently increased pyruvate metabolism (B). Treatment with meldonium fully restored mitochondrial bioenergetics (A,B) to the level of the normal control group. The results are presented as the mean±SEM of 9 animals. * p < 0.05 vs. the LPS group, one-way ANOVA with Dunnett’s multiple comparison test. Flux control factor, the contribution of each substrate/pathway to the respiration rate; p, pyruvate; S, succinate; F, FA oxidation-dependent pathway; N, NADH pathway; LEAK, substrate-dependent state; OXPHOS, oxidative phosphorylation-dependent state; ROX, residual oxygen consumption.

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  Figure 6. Chemical structure of meldonium.

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  Figure 7. Schematic representation of the study design. MCT, monocrotaline; LPS, lipopolysaccharide.