Human αB-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice

Namakkal S. Rajasekaran, Patrice Connell, Elisabeth S. Christians, Liang Jun Yan, Ryan P. Taylor, András Orosz, Xiu Q. Zhang, Tamara J. Stevenson, Ronald M. Peshock, Jane A. Leopold, William H. Barry, Joseph Loscalzo, Shannon J. Odelberg, Ivor J. Benjamin

Research output: Contribution to journalArticlepeer-review

306 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)427-439
Number of pages13
JournalCell
Volume130
Issue number3
DOIs
StatePublished - 10 Aug 2007

Keywords

  • HUMDISEASE
  • SIGNALING

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