The study of cardiomyocytes mitochondrial dysfunction in hyperhomocysteinemia and nitric oxyde deficiency

Abstract

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.