Gobinath Shanmugam1, Ding Wang2, Sellamuthu S Gounder3, Jolyn Fernandes4, Silvio H Litovsky1, Kevin Whitehead3, Rajesh Kumar Radhakrishnan1, Sarah Franklin3, John R Hoidal5, Thomas W Kensler6, Louis Dell'Italia7, Victor Darley-Usmar8, E Dale Abel9, Dean P Jones4, Peipei Ping2,10, Namakkal S Rajasekaran1,3,8,11. 1. Cardiac Aging and Redox Signaling Laboratory, Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA. 2. Department of Physiology, NIH BD2K Center of Excellence for Biomedical Computing at UCLA, University of California, Los Angeles, California, USA. 3. Division of Cardiovascular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA. 4. Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, Georgia, USA. 5. Pulmonary Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA. 6. Fred Hutch Cancer Research Center, Seattle, Washington, USA. 7. Comprehensive Cardiovascular Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. 8. Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA. 9. Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. 10. Department of Medicine/Cardiology, NHLBI Integrated Cardiovascular Data Science Training Program at UCLA, Bioinformatics and Medical Informatics, and Scalable Analytics Institute (ScAi) at UCLA School of Engineering, Los Angeles, California, USA. 11. Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Abstract
Aims: Redox homeostasis is tightly controlled and regulates key cellular signaling pathways. The cell's antioxidant response provides a natural defense against oxidative stress, but excessive antioxidant generation leads to reductive stress (RS). This study elucidated how chronic RS, caused by constitutive activation of nuclear erythroid related factor-2 (caNrf2)-dependent antioxidant system, drives pathological myocardial remodeling. Results: Upregulation of antioxidant transcripts and proteins in caNrf2-TG hearts (TGL and TGH; transgenic-low and -high) dose dependently increased glutathione (GSH) redox potential and resulted in RS, which over time caused pathological cardiac remodeling identified as hypertrophic cardiomyopathy (HCM) with abnormally increased ejection fraction and diastolic dysfunction in TGH mice at 6 months of age. While the TGH mice exhibited 60% mortality at 18 months of age, the rate of survival in TGL was comparable with nontransgenic (NTG) littermates. Moreover, TGH mice had severe cardiac remodeling at ∼6 months of age, while TGL mice did not develop comparable phenotypes until 15 months, suggesting that even moderate RS may lead to irreversible damages of the heart over time. Pharmacologically blocking GSH biosynthesis using BSO (l-buthionine-SR-sulfoximine) at an early age (∼1.5 months) prevented RS and rescued the TGH mice from pathological cardiac remodeling. Here we demonstrate that chronic RS causes pathological cardiomyopathy with diastolic dysfunction in mice due to sustained activation of antioxidant signaling. Innovation and Conclusion: Our findings demonstrate that chronic RS is intolerable and adequate to induce heart failure (HF). Antioxidant-based therapeutic approaches for human HF should consider a thorough evaluation of redox state before the treatment.
Aims: Redox homeostasis is tightly controlled and regulates key cellular signaling pathways. The cell's antioxidant response provides a natural defense against oxidative stress, but excessive antioxidant generation leads to reductive stress (RS). This study elucidated how chronic RS, caused by constitutive activation of nuclear erythroid related factor-2 (caNrf2)-dependent antioxidant system, drives pathological myocardial remodeling. Results: Upregulation of antioxidant transcripts and proteins in caNrf2-TG hearts (TGL and TGH; transgenic-low and -high) dose dependently increased glutathione (GSH) redox potential and resulted in RS, which over time caused pathological cardiac remodeling identified as hypertrophic cardiomyopathy (HCM) with abnormally increased ejection fraction and diastolic dysfunction in TGH mice at 6 months of age. While the TGH mice exhibited 60% mortality at 18 months of age, the rate of survival in TGL was comparable with nontransgenic (NTG) littermates. Moreover, TGH mice had severe cardiac remodeling at ∼6 months of age, while TGL mice did not develop comparable phenotypes until 15 months, suggesting that even moderate RS may lead to irreversible damages of the heart over time. Pharmacologically blocking GSH biosynthesis using BSO (l-buthionine-SR-sulfoximine) at an early age (∼1.5 months) prevented RS and rescued the TGH mice from pathological cardiac remodeling. Here we demonstrate that chronic RS causes pathological cardiomyopathy with diastolic dysfunction in mice due to sustained activation of antioxidant signaling. Innovation and Conclusion: Our findings demonstrate that chronic RS is intolerable and adequate to induce heart failure (HF). Antioxidant-based therapeutic approaches for human HF should consider a thorough evaluation of redox state before the treatment.
Authors: Goran Bjelakovic; Dimitrinka Nikolova; Lise Lotte Gluud; Rosa G Simonetti; Christian Gluud Journal: JAMA Date: 2007-02-28 Impact factor: 56.272
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Authors: Justin M Quiles; Mark E Pepin; Sini Sunny; Sandeep B Shelar; Anil K Challa; Brian Dalley; John R Hoidal; Steven M Pogwizd; Adam R Wende; Namakkal S Rajasekaran Journal: Sci Rep Date: 2021-06-07 Impact factor: 4.379