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Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice

Namakkal S Rajasekaran1, Patrice Connell, Elisabeth S Christians

  • 1Center for Cardiovascular Translational Biomedicine, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.

Cell
|August 19, 2007
PubMed

Insights

A mutation in the alphaB-crystallin gene causes heart disease. Reducing glucose-6-phosphate dehydrogenase (G6PD) activity in mice prevented this cardiomyopathy, suggesting G6PD as a therapeutic target.

Area of Science:

  • Cardiovascular Biology
  • Molecular Genetics
  • Biochemistry

Background:

  • Autosomal dominant mutation in the alphaB-crystallin gene (R120G) causes multisystem protein aggregation diseases, including cardiomyopathy.
  • The precise mechanisms driving cardiomyopathy in hR120GCryAB mutant are not fully understood.

Purpose of the Study:

  • To investigate the pathogenesis of hR120GCryAB-induced cardiomyopathy.
  • To identify potential therapeutic targets for R120GCryAB cardiomyopathy.

Main Methods:

  • Generated transgenic mice overexpressing cardiac-specific hR120GCryAB.
  • Analyzed cardiac tissue for signs of reductive stress and alterations in glutathione metabolism.
  • Intercrossed hR120GCryAB mice with mice having reduced glucose-6-phosphate dehydrogenase (G6PD) levels.

Main Results:

  • Transgenic mice exhibited cardiomyopathy mirroring human conditions and displayed signs of reductive stress.
  • Myopathic hearts showed increased glutathione recycling due to elevated glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, and glutathione peroxidase.
  • Reducing G6PD levels in hR120GCryAB mice rescued cardiac hypertrophy and protein aggregation.

Conclusions:

  • Dysregulation of G6PD activity is critical for maladaptive reductive stress in R120GCryAB cardiomyopathy.
  • Targeting G6PD activity presents a novel therapeutic strategy for R120GCryAB cardiomyopathy and human heart failure.

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