Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction.
Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction.
复制标题
DOI：
10.1093/cvr/cvn182
复制
发表时间：
2008-11
影响因子：
10.8
通讯作者：
P. Wenzel;Swenja Schuhmacher;J. Kienhöfer;Johanna Müller;M. Hortmann;M. Oelze;Eberhard Schulz;N. Tr
中科院分区：
文献类型：
--
作者：
P. Wenzel;Swenja Schuhmacher;J. Kienhöfer;Johanna Müller;M. Hortmann;M. Oelze;Eberhard Schulz;N. Tr
目的前体和抗氧化剂之间的失衡(如在衰老过程中)对血管功能起着至关重要的作用，并与氧化基因的调节和修饰有关。血管老化与血管稳态的进行性恶化有关，导致松弛减少、肥厚，并增加血栓事件的风险。这些效应可以用自由生物可用一氧化氮的减少来解释，而自由生物可用一氧化氮的减少是由年龄相关的超氧化物形成的增加而失活的。本研究探讨了线粒体作为活性氧(ROS)的来源以及锰超氧化物歧化酶(MnSOD，SOD-2)和乙醛脱氢酶(ALDH-2)的贡献。方法和结果通过器官室内等长张力测定，观察C57/BL6野生型(WT)、ALDH-2(-/-)、MnSOD(+/+)和MnSOD(+/-)小鼠主动脉血管功能的增龄效应。用鲁米诺(L)增强的化学发光法测定线粒体ROS的形成，用高效液相色谱法测定心肌线粒体2-羟乙基的形成。ROS介导的线粒体DNA(MtDNA)损伤是用一种新的改良的荧光检测碱性DNA解卷(FADU)法检测的。在老年C57/BL6WT小鼠中观察到内皮功能障碍，同时线粒体ROS形成增加和线粒体DNA氧化损伤。相反，中年ALDH-2(-/-)小鼠表现出与老年ALDH-2(-/-)小鼠相似的显著血管功能障碍，表明ALDH-2发挥年龄依赖性的血管保护作用。老龄MnSOD(+/-)小鼠表现出最明显的表型，如血管松弛严重受损，线粒体ROS形成水平最高，mtDNA损伤。结论mtROS的形成与乙酰胆碱依赖的松弛有关，线粒体自由基的形成在年龄依赖性内皮功能障碍中起重要作用。
AIMS Imbalance between pro- and antioxidant species (e.g. during aging) plays a crucial role for vascular function and is associated with oxidative gene regulation and modification. Vascular aging is associated with progressive deterioration of vascular homeostasis leading to reduced relaxation, hypertrophy, and a higher risk of thrombotic events. These effects can be explained by a reduction in free bioavailable nitric oxide that is inactivated by an age-dependent increase in superoxide formation. In the present study, mitochondria as a source of reactive oxygen species (ROS) and the contribution of manganese superoxide dismutase (MnSOD, SOD-2) and aldehyde dehydrogenase (ALDH-2) were investigated. METHODS AND RESULTS Age-dependent effects on vascular function were determined in aortas of C57/Bl6 wild-type (WT), ALDH-2(-/-), MnSOD(+/+), and MnSOD(+/-) mice by isometric tension measurements in organ chambers. Mitochondrial ROS formation was measured by luminol (L-012)-enhanced chemiluminescence and 2-hydroxyethidium formation with an HPLC-based assay in isolated heart mitochondria. ROS-mediated mitochondrial DNA (mtDNA) damage was detected by a novel and modified version of the fluorescent-detection alkaline DNA unwinding (FADU) assay. Endothelial dysfunction was observed in aged C57/Bl6 WT mice in parallel to increased mitochondrial ROS formation and oxidative mtDNA damage. In contrast, middle-aged ALDH-2(-/-) mice showed a marked vascular dysfunction that was similar in old ALDH-2(-/-) mice suggesting that ALDH-2 exerts age-dependent vasoprotective effects. Aged MnSOD(+/-) mice showed the most pronounced phenotype such as severely impaired vasorelaxation, highest levels of mitochondrial ROS formation and mtDNA damage. CONCLUSION The correlation between mtROS formation and acetylcholine-dependent relaxation revealed that mitochondrial radical formation significantly contributes to age-dependent endothelial dysfunction.