Regulation of lipid peroxidation in mitochondria by nitroglycerine

Abstract

The mechanisms of lipid oxidation under the application of nitroglycerine (NG) were studied in isolated rat heart and liver mitochondria. Dose-dependent formation of diene conjugates (DC), leukotriene C4 (LTC4) and thromboxane B2 (TxB2) was shown. To disclose the mechanisms regulating lipid peroxidation in mitochondria, we studied the effect of NG application on the formation of prooxidants (H2O2 and free Fe2+), as well as xanthine oxidase and mtNOS activity as main sources of ROS and RNS. Based on the correlation dependences, we have found that DC, LTC4, and TxB2 formation was strongly dependent on hydroperoxide production and free divalent iron release in mitochondria. Also, DC formation exhibited the dependence on Ca2+ uptake in mitochondria. No dependence of lipid oxidation on xanthine oxidase activity was found. In heart, but not liver mitochondria, DC, LTC4, and TxB2 exhibited strong dependence on mtNOS activity, but were independent of nitrosothiols formation. This indicated that lipid oxidation was independent of direct protein nitrosylation caused by NG application. No dependence of lipid oxidation on mtNOS activity in liver was found, which agreed with much higher mtNOS activity in heart mitochondria, and suppression of mtNOS activity in liver mitochondria at high doses of NG. So, we came to the conclusion that under NG application ROS overproduction and free Fe2+ release promoted both enzymatic and non-enzymatic lipid oxidation in heart and liver mitochondria. Also, we hypothesized that RNS overproduction due to the elevated mtNOS activity in the heart could largely contribute to lipid peroxidation and promote much faster increase in the formation of lipid oxidation products in heart as compared to liver mitochondria, especially at high doses of NG. Obtained correlation dependences allowed us disclose free iron, hydroperoxide, and mtNOS activity as principal factors affecting lipid peroxidation in mitochondria under NG application.