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.
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.
Division of Cardiology, Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA. raj.soorappan@hsc.utah.edu
Namakkal Soorappan
NS
Rajasekaran
Saradhadevi
S
Varadharaj
Gayatri D
GD
Khanderao
Christopher J
CJ
Davidson
Sankaranarayanan
S
Kannan
Matthew A
MA
Firpo
Jay L
JL
Zweier
Ivor J
IJ
Benjamin
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; C059215:CRYAB protein, human; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D038203:alpha-Crystallin B Chain