Many people take antioxidants in hopes of preventing heart disease, but University of Utah researchers have found that too much of one antioxidant, reduced glutathione, may lead to "reductive stress" heart disease.

They hope their findings, published today in Cell, will lead to a new class of drugs to prevent or treat some heart disease, said Dr. Ivor J. Benjamin, division chief of cardiology at the U. School of Medicine and lead author for the study.

It flies in the face of some scientific thinking, he said. "It's a paradigm shift going up against the dogma of oxidative stress and antioxidants. We've come up with almost a contrarian view."

A protein called alpha B-Crystallin usually helps long strips of various proteins fold inside cells, which then produce the right amount of reduced glutathione. In the mouse model the researchers used, they found that a mutation of the protein triggers abnormal folding that creates excessive amounts of the antioxidant, which clumps, similar to what milk does when it sours.

It is a condition that causes heart disease, muscle and respiratory weakness, as well as cataracts, because those are the different tissues in which the mutant protein is expressed, Benjamin said. They focused on the heart and the resulting condition, reductive stress.

In the mice that developed heart failure because of the mutant protein, the researchers found increased activity of the biochemical pathway leads to an increase in the antioxidant. Then they examined whether lowering one of the key enzymes in the pathway in the animals prone to heart failure would help. It did.

That shows, among other things, Benjamin said, that "just because we see oxidative stress, it's not necessarily a problem that can be solved with an antioxidant." He hopes it will stimulate research both in the lab and in patients to see if an exaggerated amount of the reductive equivalent contributes to heart disease and, by implication, other diseases that involve folding disorders, including degenerative ones like Parkinson's and Lou Gehrig's disease.

"All of these conditions are associated with activation of stress-response pathways .... This is a condition in which antioxidative pathways that are normally beneficial for you have gone to the extreme."

Glutathione, one of the body's most powerful antioxidants, is primarily regulated by an enzyme called G6PD. 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. Their babies had normal levels of the antioxidant and didn't develop heart failure.

They headed off heart disease not by preventing the gene mutation, but by correcting its consequence, sparking hope that drugs can be developed to do that, too, by going after the genetic pathway, Benjamin said.