Human [alpha]B-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.06.044 Byline: Namakkal S. Rajasekaran (1), Patrice Connell (2), Elisabeth S. Christians (2)(3), Liang-Jun Yan (2), Ryan P. Taylor (1), Andras 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), Ivor J. Benjamin (1)(2) Keywords: HUMDISEASE; SIGNALING Abstract: The autosomal dominant mutation in the human [alpha]B-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. Author Affiliation: (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 Article History: Received 25 January 2007; Revised 26 April 2007; Accepted 22 June 2007 Article Note: (miscellaneous) Published: August 9, 2007