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

Namakkal Soorappan Rajasekaran, Saradhadevi Varadharaj, Gayatri D. Khanderao, Christopher J. Davidson, Sankaranarayanan Kannan, Matthew A. Firpo, Jay L. Zweier, Ivor J. Benjamin

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)957-971
Number of pages15
JournalAntioxidants and Redox Signaling
Volume14
Issue number6
DOIs
StatePublished - Mar 15 2011
Externally publishedYes

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Antioxidant Response Elements
Mutant Proteins
Cardiomyopathies
Agglomeration
Chemical activation
Antioxidants
Proteins
Takotsubo Cardiomyopathy
Crystallins
Hypertrophic Cardiomyopathy
Missense Mutation
Heat-Shock Proteins
Oligomerization
Hypertrophy
Transcriptional Activation
Reactive Oxygen Species
Transcription Factors
Up-Regulation
Molecular Weight
Assays

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

Cite this

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. / Rajasekaran, Namakkal Soorappan; Varadharaj, Saradhadevi; Khanderao, Gayatri D.; Davidson, Christopher J.; Kannan, Sankaranarayanan; Firpo, Matthew A.; Zweier, Jay L.; Benjamin, Ivor J.

In: Antioxidants and Redox Signaling, Vol. 14, No. 6, 15.03.2011, p. 957-971.

Research output: Contribution to journalArticle

Rajasekaran, Namakkal Soorappan ; Varadharaj, Saradhadevi ; Khanderao, Gayatri D. ; Davidson, Christopher J. ; Kannan, Sankaranarayanan ; Firpo, Matthew A. ; Zweier, Jay L. ; Benjamin, Ivor J. / 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. In: Antioxidants and Redox Signaling. 2011 ; Vol. 14, No. 6. pp. 957-971.
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