Cell：抗氧化剂过量可能引发人类遗传性疾病
生物谷报道：尽管有许多人承认这样一种观点，即类似维生素C和E的抗氧化剂，因为可以保护机体免受损伤性自由基的伤害，具有维护健康的作用。但是发表在8月10日Cell杂志上的文章揭露，事实上，平衡才是关键。研究者通过实验发现，这些自然的抗氧化剂的过量，在小鼠中会引发心脏病。
有许多研究都已表明氧化应激（oxidative stress）会造成的各种损伤，但是“硬币拥有着另外一面，” 犹他大学的Ivor Benjamin解释道，“还原剂的过量同样会造成损伤。”
还原剂（reductant），有时又名抗氧化剂，是一类比较容易失去电子而被“氧化”的单质或化合物。氧化剂（oxidizing agent）正是接受电子的物质。在机体内，此类氧化还原反应（oxidation-reduction reaction；redox reaction）是能量释放和储存的中心枢纽，许多细胞通路对氧化还原的环境非常敏感。
氧化应激时，还原剂相对缺乏，这早已被研究认为对许多心脏或其他的疾病负责。但反过来，如果天平偏向另一头，那么也同样会造成还原应激（reductive stress），这也会造成严重的伤害。但现有的研究仅仅停留在了低等生物体上，对于哺乳动物或者疾病的研究还很缺乏，此项研究可谓填补了这方面的空白。
原始出处:
Cell, Vol 130, 427-439, 10 August 2007
Article
Human αB-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice
Namakkal S. Rajasekaran,1 Patrice Connell,2 ELISAbeth S. Christians,2,3 Liang-Jun Yan,2 Ryan P. Taylor,1 András Orosz,1 Xiu Q. Zhang,1 Tamara J. Stevenson,1 Ronald M. Peshock,2,4 Jane A. Leopold,5 William H. Barry,1 Joseph Loscalzo,5 Shannon J. Odelberg,1 and Ivor J. Benjamin1,2,
1 Center for Cardiovascular Translational Biomedicine, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, 30 North 1900 East, Room 4A100, Salt Lake City, UT 84132, USA
2 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
3 Centre for Developmental Biology UMR5547, 118 route de Narbonne, 31062 Toulouse, France
4 Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
5 Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur Boston, MA 02115, USA
Corresponding author
Ivor J. Benjamin
ivor.benjamin@hsc.utah.edu
The autosomal dominant mutation in the human αB-crystallin gene inducing a R120G amino acid exchange causes a multisystem, protein aggregation disease including cardiomyopathy. The pathogenesis of cardiomyopathy in this mutant (hR120GCryAB) is poorly understood. Here, we show that transgenic mice overexpressing cardiac-specific hR120GCryAB recapitulate the cardiomyopathy in humans and find that the mice are under reductive stress. The myopathic hearts show an increased recycling of oxidized glutathione (GSSG) to reduced glutathione (GSH), which is due to the augmented expression and enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, and glutathione peroxidase. The intercross of hR120GCryAB cardiomyopathic animals with mice with reduced G6PD levels rescues the progeny from cardiac hypertrophy and protein aggregation. These findings demonstrate that dysregulation of G6PD activity is necessary and sufficient for maladaptive reductive stress and suggest a novel therapeutic target for abrogating R120GCryAB cardiomyopathy and heart failure in humans.
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