Mutant mice with an abundance of reduced glutathione and mutated alpha B-Crystallin developed heart failure, but offspring with average reduced glutathione and mutated protein didn’t.

Excessive levels of one antioxidant called reduced glutathione may actually contribute to heart disease, according to University of Utah researchers.

The protein alpha B-Crystallin normally helps long strips of other proteins fold inside cells. When the gene that makes alpha B-Crystallin is mutated in humans, proteins fold improperly into aggregrates, leading to a number of diseases.

In a study of laboratory mice with failing hearts caused by mutant alpha B-Crystallin, the Utah team measured oxidative stress expecting to see higher than normal levels. Instead, they found the mice had markedly reduced oxidative stress 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 also have been documented in human heart failure. Such stress responses yield reactive oxygen species, triggering antioxidative pathways to kick in, including increasing the enzyme glucose-6-phosphate dehydrogenase (G6PD), which regulates glutathione oxidation.

In these diseased animals, however, the pathway in which oxidized glutathione is recycled to its reduced antioxidant form soon got out of hand, producing excess levels of G6PD and thus larger amounts of reduced glutathione, causing a condition of reductive stress.

To determine the connection between reduced glutathione and heart failure, the team mated mutant alpha B-Crystallin mice that carried too much G6PD with mice that had significantly lower levels of the enzyme. The resulting offspring contained the mutant gene for alpha B-Crystallin but 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,” says Ivor Benjamin, M.D., of the University of Utah. “Basically, we prevented them from getting heart failure.”

The study is published in the August 10 issue of Cell.

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