Trimethylamine N-oxide impairs pyruvate and fatty acid oxidation in cardiac mitochondria
Trimethylamine N-oxide impairs pyruvate and fatty acid oxidation in cardiac mitochondria
复制标题
DOI：
10.1016/j.toxlet.2016.12.017
复制
发表时间：
2017-02-05
影响因子：
3.5
通讯作者：
Dambrova, Maija
中科院分区：
文献类型：
--
作者：
Makrecka-Kuka, Marina;Volska, Kristine;Dambrova, Maija
促动脉粥样硬化代谢物三甲胺N-氧化物（TMAO）的血浆浓度增加与不良心血管结局有关;然而，目前尚不清楚TMAO是否是一种生物标志物或是否会引起直接有害的心血管效应。由于改变的心脏能量代谢和线粒体功能障碍在心血管疾病的发展中起着至关重要的作用，我们假设增加的TMAO浓度可能改变线粒体能量代谢。本研究的目的是确定TMAO对心肌线粒体能量代谢的影响。心脏纤维急性暴露于TMAO降低了丙酮酸的LEAK（底物依赖性）和OXPHOS（氧化磷酸化依赖性）线粒体呼吸，并通过丙酮酸脱氢酶损害底物通量。以120 mg/kg的剂量施用TMAO 8周，使血浆和心脏组织中的TMAO浓度分别增加22-23倍至约15 μ M和11 nmol/g。长期TMAO给药使丙酮酸的线粒体] LEAK状态呼吸降低30%，而不影响OXPHOS状态呼吸。然而，在生理条件下急性暴露于TMAO后，未观察到心肌纤维线粒体活性氧产生的显著变化。此外，长期TMAO给药和急性暴露于TMAO均降低了棕榈酰辅酶A的呼吸，表明β-氧化受损。两者合计，我们的结果表明，增加TMAO浓度损害丙酮酸和脂肪酸氧化在心肌线粒体。因此，TMAO在心脏组织中的积累导致能量代谢紊乱，这可能增加心血管事件的严重性。(C)2016爱思唯尔爱尔兰有限公司版权所有。
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.