期刊
TOXICOLOGY LETTERS
卷 267, 期 -, 页码 32-38出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2016.12.017
关键词
Trimethylamine N-oxide; Cardiac mitochondria; Energy metabolism; Reactive oxygen species
类别
资金
- Latvian State Research Program BIOMEDICINE
- Riga Stradins University [RSU ZP 09/2013]
- FP7 project InnovaBalt
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 mitochondria] energy metabolism. The aim of the present study was to determine the effects of TMAO on cardiac mitochondria] energy metabolism. Acute exposure of cardiac fibers to TMAO decreased LEAK (substrate-dependent) and OXPHOS (oxidative phosphorylation-dependent) mitochondria] 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 mu M and 11 nmol/g, respectively. Long-term TMAO administration decreased mitochondria] LEAK state respiration with pyruvate by 30% without affecting OXPHOS state respiration. However, no significant changes in mitochondria] 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 beta-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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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