生物谷報(bào)道：盡管有許多人承認(rèn)這樣一種觀點(diǎn),，即類似維生素C和E的抗氧化劑,，因?yàn)榭梢员Ｗo(hù)機(jī)體免受損傷性自由基的傷害,，具有維護(hù)健康的作用,。但是發(fā)表在8月10日Cell雜志上的文章揭露,，事實(shí)上,，平衡才是關(guān)鍵。研究者通過實(shí)驗(yàn)發(fā)現(xiàn),，這些自然的抗氧化劑的過量,，在小鼠中會(huì)引發(fā)心臟病。
有許多研究都已表明氧化應(yīng)激（oxidative stress）會(huì)造成的各種損傷,，但是“硬幣擁有著另外一面,，” 猶他大學(xué)的Ivor Benjamin解釋道，“還原劑的過量同樣會(huì)造成損傷,。”
還原劑（reductant）,，有時(shí)又名抗氧化劑，是一類比較容易失去電子而被“氧化”的單質(zhì)或化合物,。氧化劑（oxidizing agent）正是接受電子的物質(zhì),。在機(jī)體內(nèi)，此類氧化還原反應(yīng)（oxidation-reduction reaction,；redox reaction）是能量釋放和儲存的中心樞紐,，許多細(xì)胞通路對氧化還原的環(huán)境非常敏感。
氧化應(yīng)激時(shí),，還原劑相對缺乏,，這早已被研究認(rèn)為對許多心臟或其他的疾病負(fù)責(zé)。但反過來,，如果天平偏向另一頭,，那么也同樣會(huì)造成還原應(yīng)激（reductive stress），這也會(huì)造成嚴(yán)重的傷害,。但現(xiàn)有的研究僅僅停留在了低等生物體上,，對于哺乳動(dòng)物或者疾病的研究還很缺乏，此項(xiàng)研究可謂填補(bǔ)了這方面的空白,。
原始出處:
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
[email protected]
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.
