TY - JOUR
T1 - Reductive Stress Causes Pathological Cardiac Remodeling and Diastolic Dysfunction
AU - Shanmugam, Gobinath
AU - Wang, Ding
AU - Gounder, Sellamuthu S.
AU - Fernandes, Jolyn
AU - Litovsky, Silvio H.
AU - Whitehead, Kevin
AU - Radhakrishnan, Rajesh Kumar
AU - Franklin, Sarah
AU - Hoidal, John R.
AU - Kensler, Thomas W.
AU - Dell'Italia, Louis
AU - Darley-Usmar, Victor
AU - Abel, E. Dale
AU - Jones, Dean P.
AU - Ping, Peipei
AU - Rajasekaran, Namakkal S.
N1 - Publisher Copyright:
© Copyright 2020, Mary Ann Liebert, Inc., publishers 2020.
PY - 2020/6/20
Y1 - 2020/6/20
N2 - 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.
AB - 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.
KW - HCMiEF
KW - Nrf2
KW - cardiac hypertrophy
KW - diastolic dysfunction
KW - reductive stress
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U2 - 10.1089/ars.2019.7808
DO - 10.1089/ars.2019.7808
M3 - Article
C2 - 32064894
AN - SCOPUS:85085085766
SN - 1523-0864
VL - 32
SP - 1293
EP - 1312
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 18
ER -