Makrecka-Kuka Marina, Volska Kristine, Antone Unigunde, Vilskersts Reinis, Grinberga Solveiga, Bandere Dace, Liepinsh Edgars, Dambrova Maija
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia; Riga Stradins University, Faculty of Pharmacy, Dzirciema Str. 16, Riga, LV-1007, Latvia.
Toxicol Lett. 2017 Feb 5;267:32-38. doi: 10.1016/j.toxlet.2016.12.017. Epub 2016 Dec 31.
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 120mg/kg for 8 weeks increased TMAO concentration in plasma and cardiac tissues 22-23 times to about 15μM and 11nmol/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.
三甲胺 N-氧化物（TMAO）是一种促动脉粥样硬化代谢产物，其血浆浓度升高与不良心血管结局相关；然而，TMAO 究竟是一种生物标志物，还是会引发直接的心血管有害作用，仍不明确。由于心脏能量代谢改变和线粒体功能障碍在心血管疾病发展过程中起关键作用，我们推测 TMAO 浓度升高可能会改变线粒体能量代谢。本研究的目的是确定 TMAO 对心脏线粒体能量代谢的影响。心脏纤维急性暴露于 TMAO 会降低丙酮酸的 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 120mg/kg 的剂量给予 TMAO 8 周，可使血浆和心脏组织中的 TMAO 浓度分别增加 22 - 23 倍，达到约 15μM 和 11nmol/g。长期给予 TMAO 可使丙酮酸的线粒体 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，心脏纤维急性暴露于 TMAO 后，未观察到线粒体活性氧产生有显著变化。此外，长期给予 TMAO 和急性暴露于 TMAO 均会降低棕榈酰辅酶 A 的呼吸，表明β-氧化受损。综上所述，我们的结果表明，TMAO 浓度升高会损害心脏线粒体中的丙酮酸和脂肪酸氧化。因此，TMAO 在心脏组织中的积累会导致能量代谢紊乱，进而增加心血管事件的严重程度。
