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Reductive stress linked to heart disease

SALT LAKE CITY -- Antioxidants are widely considered an important defense against heart disease, but University of Utah researchers have found excessive levels of one antioxidantreduced glutathioneactually may contribute to the disease.

The findings, published in the Aug. 10 issue of Cell, indicate a new class of drugs can be developed to treat or even prevent heart disease caused by reductive stress, according to Ivor J. Benjamin, M.D., Christi T. Smith Chair of Cardiovascular Research, division chief of cardiology at the U School of Medicine and the studys principal author.

The protein alpha B-Crystallin, termed a molecular chaperone, normally helps long strips of other proteins fold inside cells. When it works properly, the cell produces the correct amount of reduced glutathione, which is healthy for the body. Unfortunately, when the gene that makes alpha B-Crystallin is mutated in humans, the protein unfolds improperly into aggregrates, the hallmark of the condition in different organs, including the heart. When that happens, reduced glutathione is produced in such excessive levels that it harms the heart, Benjamin said. The resulting condition is called reductive stress.

In a study of laboratory mice with failing hearts caused by mutant alpha B-Crystallin, Benjamin and several U of U colleagues found increased activity of the biochemical pathway leading to high levels of reduced glutathione in the animals.

Glutathione, one of the bodys most powerful antioxidants, is regulated at multiple steps principally by the G6PD enzyme. To establish the connection between reduced glutathione and heart failure, Benjamin mated mutant alpha B-Crystallin mice that carried too much G6PD with mice that had far lower levels. The resulting offspring had normal levels of reduced glutathione and did not develop heart failure.

Lowering the level of reduced glutathione dramatically changed the survival of these mice, Benjamin sai
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Contact: Phil Sahm
phil.sahm@hsc.utah.edu
801-581-2517
University of Utah Health Sciences Center
9-Aug-2007


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