Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Free Radic Biol Med. 2012 Mar 1;52(5):841-9. doi: 10.1016/j.freeradbiomed.2011.11.026. Epub 2011 Dec 14.
A number of recent studies suggest that mitochondrial oxidative damage may be associated with atherosclerosis and the metabolic syndrome. However, much of the evidence linking mitochondrial oxidative damage and excess reactive oxygen species (ROS) with these pathologies is circumstantial. Consequently the importance of mitochondrial ROS in the etiology of these disorders is unclear. Furthermore, the potential of decreasing mitochondrial ROS as a therapy for these indications is not known. We assessed the impact of decreasing mitochondrial oxidative damage and ROS with the mitochondria-targeted antioxidant MitoQ in models of atherosclerosis and the metabolic syndrome (fat-fed ApoE(-/-) mice and ATM(+/-)/ApoE(-/-) mice, which are also haploinsufficient for the protein kinase, ataxia telangiectasia mutated (ATM). MitoQ administered orally for 14weeks prevented the increased adiposity, hypercholesterolemia, and hypertriglyceridemia associated with the metabolic syndrome. MitoQ also corrected hyperglycemia and hepatic steatosis, induced changes in multiple metabolically relevant lipid species, and decreased DNA oxidative damage (8-oxo-G) in multiple organs. Although MitoQ did not affect overall atherosclerotic plaque area in fat-fed ATM(+/+)/ApoE(-/-) and ATM(+/-)/ApoE(-/-) mice, MitoQ reduced the macrophage content and cell proliferation within plaques and 8-oxo-G. MitoQ also significantly reduced mtDNA oxidative damage in the liver. Our data suggest that MitoQ inhibits the development of multiple features of the metabolic syndrome in these mice by affecting redox signaling pathways that depend on mitochondrial ROS such as hydrogen peroxide. These findings strengthen the growing view that elevated mitochondrial ROS contributes to the etiology of the metabolic syndrome and suggest a potential therapeutic role for mitochondria-targeted antioxidants.
一些最近的研究表明，线粒体氧化损伤可能与动脉粥样硬化和代谢综合征有关。然而，将线粒体氧化损伤与过量的活性氧（ROS）与这些病理联系起来的大部分证据都是间接的。因此，线粒体 ROS 在这些疾病的病因学中的重要性尚不清楚。此外，减少线粒体 ROS 作为这些适应症的治疗方法的潜力尚不清楚。我们评估了用线粒体靶向抗氧化剂 MitoQ 减少线粒体氧化损伤和 ROS 对动脉粥样硬化和代谢综合征模型（高脂喂养的 ApoE(-/-)小鼠和 ATM(+/-)/ApoE(-/-)小鼠，它们也对半缺失蛋白激酶 ATM（ataxia telangiectasia mutated））的影响。MitoQ 经口给药 14 周可预防代谢综合征相关的肥胖、高胆固醇血症和高三酰甘油血症。MitoQ 还纠正了高血糖和肝脂肪变性，诱导多种与代谢相关的脂质种类发生变化，并降低了多个器官中的 DNA 氧化损伤（8-oxo-G）。尽管 MitoQ 不影响高脂喂养的 ATM(+/+)/ApoE(-/-)和 ATM(+/-)/ApoE(-/-)小鼠的总动脉粥样硬化斑块面积，但 MitoQ 减少了斑块内的巨噬细胞含量和细胞增殖以及 8-oxo-G。MitoQ 还显著降低了肝脏中的 mtDNA 氧化损伤。我们的数据表明，MitoQ 通过影响依赖于线粒体 ROS（如过氧化氢）的氧化还原信号通路，抑制了这些小鼠中代谢综合征的多种特征的发展。这些发现加强了越来越多的观点，即升高的线粒体 ROS 导致代谢综合征的病因，并表明线粒体靶向抗氧化剂具有潜在的治疗作用。
