Human alphaB-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Cell Année : 2007

Human alphaB-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice.

Namakkal S Rajasekaran
  • Fonction : Auteur
Patrice Connell
  • Fonction : Auteur
Liang-Jun Yan
  • Fonction : Auteur
András Orosz
  • Fonction : Auteur
Xiu Q Zhang
  • Fonction : Auteur
Tamara J Stevenson
  • Fonction : Auteur
Ronald M Peshock
  • Fonction : Auteur
Jane A Leopold
  • Fonction : Auteur
William H Barry
  • Fonction : Auteur
Joseph Loscalzo
  • Fonction : Auteur
Shannon J Odelberg
  • Fonction : Auteur
Ivor J Benjamin
  • Fonction : Auteur

Résumé

The autosomal dominant mutation in the human alphaB-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.

Dates et versions

hal-00170674 , version 1 (10-09-2007)

Identifiants

Citer

Namakkal S Rajasekaran, Patrice Connell, Elisabeth S Christians, Liang-Jun Yan, Ryan P Taylor, et al.. Human alphaB-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice.. Cell, 2007, 130 (3), pp.427-39. ⟨10.1016/j.cell.2007.06.044⟩. ⟨hal-00170674⟩
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