Sustained activation of nuclear erythroid 2-related factor 2/antioxidant response element signaling promotes reductive stress in the human mutant protein aggregation cardiomyopathy in mice

Antioxid Redox Signal. 2011 Mar 15;14(6):957-71. doi: 10.1089/ars.2010.3587. Epub 2011 Feb 2.


Inheritable missense mutations in small molecular weight heat-shock proteins (HSP) with chaperone-like properties promote self-oligomerization, protein aggregation, and pathologic states such as hypertrophic cardiomyopathy in humans. We recently described that human mutant αB-crystallin (hR120GCryAB) overexpression that caused protein aggregation cardiomyopathy (PAC) was genetically linked to dysregulation of the antioxidant system and reductive stress (RS) in mice. However, the molecular mechanism that induces RS remains only partially understood. Here we define a critical role for the regulatory nuclear erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein (Keap1) pathway--the master transcriptional controller of antioxidants, in the pathogenesis of PAC and RS. In myopathic mice, increased reactive oxygen species signaling during compensatory hypertrophy (i.e., 3 months) was associated with upregulation of key antioxidants in a manner consistent with Nrf2/antioxidant response element (ARE)-dependent transactivation. In transcription factor assays, we further demonstrate increased binding of Nrf2 to ARE during the development of cardiomyopathy. Of interest, we show that the negative regulator Keap1 was predominantly sequestrated in protein aggregates (at 6 months), suggesting that sustained nuclear translocation of activated Nrf2 may be a contributing mechanism for RS. Our findings implicate a novel pathway for therapeutic targeting and abrogating RS linked to experimental cardiomyopathy in humans. Antioxid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antioxidants / metabolism*
  • Blotting, Western
  • Cardiomyopathies / genetics
  • Cardiomyopathies / metabolism*
  • Cytoskeletal Proteins / metabolism
  • Electron Spin Resonance Spectroscopy
  • Humans
  • Kelch-Like ECH-Associated Protein 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / genetics
  • Oxidative Stress / physiology
  • Polymerase Chain Reaction
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • alpha-Crystallin B Chain / genetics
  • alpha-Crystallin B Chain / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Antioxidants
  • CRYAB protein, human
  • Cytoskeletal Proteins
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Reactive Oxygen Species
  • alpha-Crystallin B Chain