Open AccessReductive Stress Causes Pathological Cardiac Remodeling and Diastolic Dysfunction
Author(s) -
Gobinath Shanmugam,
Ding Wang,
Sellamuthu S. Gounder,
Jolyn Fernandes,
Silvio Litovsky,
Kevin Whitehead,
Rajesh Radhakrishnan,
Sarah Franklin,
John R. Hoidal,
Thomas W. Kensler,
Louis J. Dell’Italia,
Victor DarleyUsmar,
E. Dale Abel,
Dean P. Jones,
Peipei Ping,
Namakkal S. Rajasekaran
Publication year - 2020
Publication title -
antioxidants and redox signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.277
H-Index - 190
eISSN - 1557-7716
pISSN - 1523-0864
DOI - 10.1089/ars.2019.7808
Subject(s) - oxidative stress , heart failure , glutathione , medicine , downregulation and upregulation , antioxidant , ventricular remodeling , endocrinology , autophagy , ejection fraction , cardiomyopathy , genetically modified mouse , homeostasis , transgene , pathological , diastole , pharmacology , biology , apoptosis , biochemistry , blood pressure , gene , enzyme
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.