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Increased plasma concentration of trimethylamine N -oxide (TMAO), a proatherogenic metabolite, has been linked to adverse cardiovascular outcomes; however, it remains unclear whether TMAO is a biomarker or whether it induces direct detrimental cardiovascular effects. Because altered cardiac energy metabolism and mitochondrial dysfunction play crucial roles in the development of cardiovascular diseases, we hypothesized that increased TMAO concentration may alter mitochondrial energy metabolism. The aim of the present study was to determine the effects of TMAO on cardiac mitochondrial energy metabolism. Acute exposure of cardiac fibers to TMAO decreased LEAK (substrate-dependent) and OXPHOS (oxidative phosphorylation-dependent) mitochondrial respiration with pyruvate and impaired substrate flux via pyruvate dehydrogenase. The administration of TMAO at a dose of 120 mg/kg for 8 weeks increased TMAO concentration in plasma and cardiac tissues 22–23 times to about 15 μM and 11 nmol/g, respectively. Long-term TMAO administration decreased mitochondrial LEAK state respiration with pyruvate by 30% without affecting OXPHOS state respiration. However, no significant changes in mitochondrial reactive oxygen species production were observed after acute exposure of cardiac fibers to TMAO under physiological conditions. In addition, both long-term TMAO administration and acute exposure to TMAO decreased respiration with palmitoyl-CoA indicating impaired β-oxidation. Taken together, our results demonstrate that increased TMAO concentration impairs pyruvate and fatty acid oxidation in cardiac mitochondria. Thus, the accumulation of TMAO in cardiac tissues leads to disturbances in energy metabolism that can increase the severity of cardiovascular events. [ABSTRACT FROM AUTHOR]

Objective The elevation of the levels of l -carnitine and its fatty acid esters, acylcarnitines, in tissue or plasma has been linked to the development of atherosclerosis. Recently, a potent inhibitor of l -carnitine biosynthesis and transport, methyl-γ-butyrobetaine (methyl-GBB), was discovered. In this study, we evaluated the effects of γ-butyrobetaine (GBB), l -carnitine and methyl-GBB administration on the progression of atherosclerosis. Methods Apolipoprotein E knockout (apoE −/− ) mice were treated with methyl-GBB, l -carnitine or GBB for 4 months. Following the treatment, the amount of atherosclerotic lesions, the number of immune cells in atherosclerotic lesions and the plasma lipid profile were analysed. The l -carnitine and acylcarnitine levels were determined in the aortic tissues of CD-1 outbred mice 2 weeks after treatment with methyl-GBB at the dose of 10 mg/kg. Results Treatment with methyl-GBB decreased the acylcarnitine and l -carnitine levels in the aortic tissues by seventeen- and ten-fold, respectively. Methyl-GBB treatment at a dose of 10 mg/kg reduced the size of atherosclerotic plaques by 36%. Neither l -carnitine nor GBB treatment affected the development of atherosclerosis. Conclusions Methyl-GBB administration significantly attenuated the development of atherosclerosis in apoE −/− mice. Our results demonstrate that decreasing the acylcarnitine pools can attenuate the development of atherosclerosis. [ABSTRACT FROM AUTHOR]