[PHNUTR-L] Antioxidant overload may underlie a heritable human disease

[Kathrynne Holden]

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Public release date: 9-Aug-2007
http://www.eurekalert.org/pub_releases/2007-08/cp-aom080307.php

Contact: Erin Doonan
edoonan at cell.com
617-397-2802
Cell Press

Antioxidant overload may underlie a heritable human disease

Despite the popular notion that antioxidants, such as vitamins C and E, 
offer health-promoting benefits by protecting against damaging free 
radicals, a new study in the August 10 issue of the journal Cell reveals 
that, in fact, balance is the key. The researchers show in mice that an 
overload of natural antioxidants can actually lead the heart to failure.

There is plenty of evidence about the damaging effects of oxidative 
stress, but “there is another side to the coin,” said Ivor Benjamin of 
the University of Utah, Salt Lake City. “There has been so much emphasis 
on free radicals to the exclusion of the potential consequences of 
reductants. Our study provides the first bona fide example of the role 
that reductive stress can play in disease.”

Reductants, sometimes referred to as antioxidants, are elements or 
compounds that easily give up an electron to become “oxidized,” while 
oxidizing agents readily accept electrons. In the body, such 
oxidation-reduction (redox) reactions are integral to the release and 
storage of energy. Many cellular pathways are also sensitive to the 
prevailing redox condition.

Oxidative stress, which consumes reducing equivalents, has been often 
implicated in numerous cardiac and other diseases, Benjamin noted. 
However, the possibility remained that an inverse imbalance could 
provoke reductive stress, with the potential for similar deleterious 
effects. Indeed, reductive stress had been demonstrated in simpler 
organisms but not in mammals and/or disease states, he said.

In the current study, the researchers examined mice carrying a human 
mutation earlier linked to so-called protein aggregation skeletal 
myopathies and cardiomyopathies, in which weakening skeletal and heart 
muscle contain clumps of proteins. Although the genetic basis for the 
disease had been linked to mutations in one of two genes, the mechanism 
responsible remained mysterious.

The researchers now show that mice with one of the mutant genes, 
áB-crystallin, specifically in the heart develop the same symptoms seen 
in human patients, including heart enlargement, progressive heart 
failure, and an early death. They further show that the animals’ hearts 
are under reductive stress.

The find initially took Benjamin by surprise, he said. They had 
conducted a test traditionally used to measure the level of oxidative 
stress in the animals, expecting they might see higher than normal 
levels. Instead, they found the mice had “markedly reduced” oxidative 
stress levels due to an abundance of a natural antioxidant known as 
glutathione.

The mutant mouse hearts exhibited a heightened stress response, 
including higher activity of heat shock proteins that have been 
documented in human heart failure, Benjamin explained. Such stress 
responses yield reactive oxygen species, triggering antioxidative 
pathways to kick in. In the diseased animals, however, that pathway—in 
which oxidized glutathione is recycled to its reduced, antioxidant 
form—soon got out of hand, producing excess levels of the reduced 
glutathione and a condition of reductive stress.

Moreover, they showed that the offspring of the heart-diseased animals 
and mice with lower levels of one of the antioxidant enzymes, 
glucose-6-phosphate dehydrogenase (G6PD), were relieved of their 
symptoms. That finding suggests that drugs or other treatments targeting 
the antioxidant pathway through G6PD “might modify the phenotype and the 
natural history of this inherited disorder in humans,” according to the 
researchers.

The results found in the heart suggest that reductive stress might 
underlie other diseases, as well. “Our findings open up a whole new line 
of investigation in protein aggregation diseases,” including 
neurodegenerative diseases such as Alzheimer’s and Huntington’s disease, 
Benjamin said.
###

The researchers include Namakkal S. Rajasekaran, Ryan P. Taylor, Andras 
Orosz, Xiu Q. Zhang, Tamara J. Stevenson, William H. Barry, and Shannon 
J. Odelberg of University of Utah, Salt Lake City; Patrice Connell, 
Liang-Jun Yan, and Ronald M. Peshock of University of Texas Southwestern 
Medical Center, Dallas; Elisabeth S. Christians of University of Texas 
Southwestern Medical Center, Dallas and Centre for Developmental Biology 
UMR5547, Toulouse; Jane A. Leopold and Joseph Loscalzo of Brigham and 
Women's Hospital, Harvard Medical School, Boston; Ivor J. Benjamin of 
University of Utah, Salt Lake City and University of Texas Southwestern 
Medical Center, Dallas.

An award from NHLBI (5RO1 HL63874) and Christi T. Smith Foundation 
provided support for this work.

Rajasekaran et al.: “Human aB-Crystallin Mutation Causes Oxido-Reductive 
Stress and Protein Aggregation Cardiomyopathy in Mice.” Publishing in 
Cell 130, 427–439, August 10, 2007. DOI 10.1016/j.cell.2007.06.044 
http://www.cell.com
-- 
Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
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