Hyperhomocysteinemia is a risk factor for many human diseases, including pulmonary pathologies. In this context much interest attracts secondary mitochondrial dysfunction, which is an important link in pathogenesis of diseases associated with hyperhomocysteinemia. The study was conducted using male Wistar rats. It was found that under conditions of severe hyperhomocysteinemia caused by administration of methionine, homocysteine was accumulated in lung mitochondria thus suggesting a direct toxic effect on these organelles. However, we have not observed any significant changes in the activity of mitochondrial enzymes involved in tissue respiration (succinate dehydrogenase) and oxidative phosphorylation (H+-ATPase) and of cytoplasmic lactate dehydrogenase. Also there was no accumulation of lactic acid in the cytoplasm. Animals with severe hyperhomocysteinemia had higher levels of lung mitochondrial protein carbonylation, decreased reserve-adaptive capacity, and increased superoxide dismutase activity. These results indicate that severe hyperhomocysteinemia causes development of oxidative stress in lung mitochondria, which is compensated by activation of antioxidant protection. These changes were accompanied by a decrease in the concentration of mitochondrial nitric oxide metabolites. Introduction to animals a nonselective NO-synthase inhibitor L-NAME caused similar enhancement of mitochondrial protein carbonylation. It demonstrates importance of reducing bioavailability of nitric oxide, which is an antioxidant in physiological concentrations, in the development of oxidative stress in lung mitochondria during hyperhomocysteinemia. Key words: hyperhomocysteinemia, nitric oxide, lung, oxidative stress, mitochondria.
Not only lipids, but also proteins are exposed to the action of reactive oxygen species (ROS). Oxidative modification of proteins (PBS) leads to a change in their native conformation with the formation of large aggregates, it causes inactivation of enzymes, disrupts the metabolism and functioning of cells. In addition, there is a growing interest in studying the hormone of the pineal gland called melatonin, as well as its synthetic analogues as the leading protection factors in the oxidative stress conditioned by disturbed physiological rhythms, including obesity. The peculiarities of protein peroxidation in the case of alimentary obesity, as well as the conditions affecting to this process, in contrast to lipid peroxidation (LPO), have not been studied sufficiently, that has determined the purpose of this study. Aim. To evaluate the effect of exogenous melatonin on the oxidative status and features of PBS in rats with alimentary obesity. Methods. The study was conducted on 27 white Wistar male rats with body weight 160180 grams. Animals were divided into 3 series of 9 rats in each: 1 series intact animals; 2 series animals with alimentary obesity, followed by the introduction of 0,9% sodium chloride solution in a volume of 2 ml for 12 days; 3 series animals with alimentary obesity followed by melatonin administration at a dose of 2 mg / kg rats for 12 days. Alimentary obesity was reproduced by feeding animals with high-calorie carbohydrate-fatty food, consisting of a laboratory feed "Assortment Agro" (42.5%), butter (25%) and sweet condensed milk (32.5%) for seven weeks. The maximum physical working capacity and resistance of rats to severe hypobaric hypoxia were determined. PBS was determined by the method of R. Levine in the modification of E.E. Dubinina. In addition, the lipid peroxidation marker TBA-reactive products (malonic dialdehyde MDA) was determined. Results. It has been established that the PBS in alimentary obesity is not specific, it is reflected in the increase in the areas of absorption of light from both the visible and ultraviolet of aldehyde and ketondinitrophenylhydrazones. In parallel with this, there was a marked increase in the concentration of TBA-reactive products in the blood serum in this pathology, as well as a significant decrease in the resistance of rats to hypobaric hypoxic hypoxia and maximum physical activity. The daily administration of a 2 mg/kg melatonin suspension to rats with alimentary obesity for 12 days leads to a significant decrease in the concentration of TBA-reactive products, however, the PBS is not significantly affected. Conclusion. Alimentary obesity in rats, simulated by the maintenance of animals on a high-calorie carbohydrate-fat diet, leads to an increase in the proportion of visceral fat in the body, an increase in the activity of PBS in the form of an increase in the level of carbonyl derivatives, a significant increase in the concentration of MDA, and a significant decrease in the stability of rats to hypobaric hypoxic hypoxia and maximum physical activity. When a melatonin suspension was administered at a dose of 2 mg/kg for 12 days, a stable high level of carbonyl derivatives was observed, in comparison with the intact series, which was explained by the need to use a greater concentration of the drug to increase its exposure time, which requires further study.
На сегодняшний день доказано, что у человека повышенный уровень гомоци-стеина в крови является независимым фактором риска ряда заболеваний. Для изу-чения аспектов участия гомоцистеина в повреждении органов и тканей при раз-личных заболеваниях может потребоваться моделирование на животных столь редко встречающейся у человека тяжёлой формы гипергомоцистеинемии, при ко-торой эффекты этого патогенетического фактора будут наиболее выражены. В данной статье описана методика моделирования на самцах крыс линии Wistar тя-жёлой формы гипергомоцистеинемии путём трёхнедельного внутрижелудочного введения суспензии метионина с добавлением этой аминокислоты в питьевую воду.Ключевые слова: гомоцистеин, тяжёлая гипергомоцистеинемия, моделирование.
Aim. To study the influence of nitric oxide metabolism disturbance on the development of mitochondrial dysfunction in case of hyperhomocysteinemia. Methods. The research was conducted on 32 Wistar male rats. Hyperhomocysteinemia was simulated by intragastric injection of methionine suspension prepared using starch and Tween-80 with addition of this amino acid into the drinking water. The nitric oxide deficiency was induced by intraperitoneal injection of L-Nω-nitroarginine methyl ester (L-NAME) solution. Results. Hyperhomocysteinemia is accompanied by dysfunction of cardiac cells mitochondria, manifesting in growth of cytoplasmic lactate level and development of oxidative stress with increased mitochondrial proteins carbonylation. Oxidative stress is largely compensated by the activation of the antioxidant defense system (including superoxide dismutase), as evidenced by a slight decrease of succinate dehydrogenase and H+-ATPase activity, the absence of statistically significant changes of cytoplasmic lactate dehydrogenase activity. Tween-80 showed antioxidant properties, reducing the content of protein carbonyl derivatives and superoxide dismutase activity. Nitric oxide deficiency caused by the L-NAME injection was accompanied by an inhibition of aerobic oxidation processes in cardiomyocytes mitochondria, which was proved by a significant decrease in succinate dehydrogenase activity as well as slight reduction of lactate dehydrogenase activity and lactate accumulation in the cytoplasm, and an oxidative phosphorylation reduction which manifested with a decrease of H+-ATPase activity. One reason for these changes is increased carbonylation of proteins due to high production of reactive oxygen species, which is not sufficiently compensated by increased activity of superoxide dismutase. Conclusion. Since hyperhomocysteinemia is associated with reduced concentrations of nitric oxide metabolites in cardiomyocytes mitochondria, and changes in these organelles after the administering of methionine have some similarities with those after injection of L-NAME, it can be argued that nitric oxide deficiency plays an important role in the pathogenesis of mitochondrial dysfunction of cardiomyocytes in case of hyperhomocysteinemia.
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