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Surplus Antioxidants are Pathogenic for Hearts and Skeletal Muscle


Research Highlights:

  • 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.

Many heart diseases are linked to oxidative stress, an overabundance of reactive oxygen species. The body reacts to reduce oxidative stress—where the redox teeter-totter has gone too far up—through production of endogenous antioxidants that reduce the reactive oxygen species. This balancing act is called redox homeostasis. 

But what happens if the redox teeter-totter goes too far down, creating antioxidative stress, also known as reductive stress? Rajasekaran Namakkal-Soorappan, Ph.D., associate professor in the University of Alabama at Birmingham Department of Pathology, and colleagues have found that reductive stress, or RS/AS, is also pathological. This discovery, they say, may have clinical importance in management of heart failure.

Credit : CC0 Public Domain

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.


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Authors : Gobinath Shanmugam, Ding Wang, Sellamuthu S. Gounder, Jolyn Fernandes, Silvio H. Litovsky, Kevin Whitehead, Rajesh Kumar Radhakrishnan, Sarah Franklin, John R. Hoidal, Thomas W. Kensler, Louis Dell'Italia, Victor Darley-Usmar, E. Dale Abel, Dean P. Jones, Peipei Ping, and Namakkal S. Rajasekaran