Human αB-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice
Open accessAbstract
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.
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Excessive depletion of oxidants may result in the induction of reductive stress, characterized by declined physiological functions such as suppressed mitochondrial function, cell proliferation, cardiomyopathies, and other pathologies.
“Excessive depletion of oxidants may result in the induction of reductive stress, characterized by declined physiological functions, such as suppressed mitochondrial function, cell proliferation, the occurrence of cardiomyopathies, and other pathologies (Rajasekaran et al. 2007).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Rajasekaran et al. 2007
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Self-citationRole of the Ubiquitin Proteasome System in the Heart
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- Authors
- Rajasekaran, N. S., Connell, P., Christians, E. S., Yan, L.-J., Taylor, R. P., Orosz, A., Zhang, X. Q., Stevenson, T. J., Peshock, R. M., Leopold, J. A., Barry, W. H., Loscalzo, J., Odelberg, S. J., & Benjamin, I. J.
- Affiliations
- University of Utah (US)
- The University of Texas Southwestern Medical Center (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Benjamin, Ivor J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 130
- Issue
- 3
- Pages
- 427-439
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2962423
- OpenAlex
- W1982561342
- Cited by
- 437
- References
- 48
- Citations by year
- 2026: 17 · 2025: 14 · 2024: 16 · 2023: 16 · 2022: 28 · 2021: 25 · 2020: 31 · 2019: 24 · 2018: 16 · 2017: 22 · 2016: 16 · 2015: 31 · 2014: 26 · 2013: 27 · 2012: 31
- FWCI
- 9.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2213 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- National Institutes of Health (DP1OD006438, 5r01hl063834-06)
- National Heart, Lung, and Blood Institute (R01 HL063834, 5R01 HL63874)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Keywords
- alphaB-crystallin, cardiomyopathy, protein aggregation, oxidative stress, reductive stress, glutathione recycling, glucose-6-phosphate dehydrogenase, glutathione reductase, glutathione peroxidase, cardiac hypertrophy, transgenic mice, heart failure, therapeutic target
- MeSH terms
- Animals, Arginine, Glucosephosphate Dehydrogenase, Glutathione, Glycine, Humans, Mice, Transgenic, Cardiomyopathies, Oxidation-Reduction, Proteins, Oxidative Stress, Mutation, Missense, alpha-Crystallin B Chain, Mice
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