Connection between reduced glutathione and heart failure

Antioxidants are widely considered an important defense against heart disease, but University of Utah researchers have found excessive levels of one antioxidant - reduced glutathione - actually 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 study's 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 body's 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 said. “Basically, we prevented them from getting heart failure.”

Heart, Alzheimer's, Parkinson's, and other deadly diseases are associated with oxidative stress, in which “free radical” molecules are produced in reaction to oxygen intake. Free radicals travel the body, triggering chemical reactions that damage proteins and causing them to form aggregates. Many people take antioxidants to prevent heart and other protein-aggregate diseases, but there actually is scant evidence to prove they work, according to Benjamin.

Until now, reductive stress has not been looked at in the context of disease. “This is a case of too much of a good thing,” Benjamin said. “Our findings indicate reductive stress warrants a more thorough investigation.”

By lowering the levels of reduced glutathione without the altering mutant gene encoding thee alpha B-Crystallin, , the study shows reductive stress can be addressed through new drugs that target the genetic pathway causing the problem, according to Benjamin.

“This field of medicine has not appreciated reductive stress and its influence on disease,” he said. “This is about balance needed in the environment of our cells, and it can have profound consequences on the treatments of heart disease and other serious disorders.”

Co-authors on the study include: Namakkal S. Rajasekaran, Ph.D, Andras Orosz, Ph.D., Ryan P. Taylor, Ph.D., Xia Q. Zhang, Ph.D., Tamara J. Stevenson, William H. Barry, M.D., and Shannon J. Oldelberg, Ph.D, all University of Utah School of Medicine; Patrice Connell, Ph.D., Liang-Jun Yan, Ph.D., Elisabeth S. Christians, D.V.M., Ph.D., and Ronald M. Peshock, M.D., the University of Texas Southwestern Medical Center, Dallas; and Jane A. Leopold, M.D., and Joseph Loscalzo, M.D., Ph.D., Harvard Medical School. Christians also is associated with the Centre for Developmental Biology, Toulouse, France.

Comments

  1. george george New Zealand says:

    There is not even a suggestion here that human heart disease involves this gene, or an excess of GSH. In fact, when the redox balance is tested in human heart disease, there is usually, or always, oxidative stress. Mice, unlike humans, make their own vitamin C, lots of it, which has to make a difference.

    Homocysteine is the rogue antioxidant in human heart disease, reducing poorly liganded copper and iron, which then generate oxidative stress and neutralise nitric oxide, NO, to ONOO. This constricts blood vessels and oxidises cholesterol.

  2. george george New Zealand says:

    selenium deficiency is a common factor in heart disease in low-selenium areas, selenium is essential for glutathione peroxidase which oxidises reduced glutathione enzymatically while neutralising lipid peroxides. so it is possible that a higher ratio of GSH to GSSG might exist in some areas due to selenium deficiency.
    Just because the protein makes more reduced glutathione (GSH) it does not mean that this stays reduced; it is the GSH-GSSG ratio that matters. estimates of the ratio in healthy cells vary from 99-1 to 500-1. Such a high ratio of reduced to oxidised glutathione, normally, makes it hard to accept reductive stress as a realistic concept. It could exist in plasma, where an oxidising environment is needed to sustain S-S bonds, but GSH in plasma is sparse, and the main effect would probably be related to low insulin if reductive stress could exist. The fact is that humans who try to elevate levels of reduced glutathione by various means do not tend to suffer heart disease as a result; if anything, the opposite is true. But selenium is essential to utilise GSH properly, and selenium levels in food from over-farmed soil have declined significantly since the 1960s.

  3. george george New Zealand says:

    http://www.ncbi.nlm.nih.gov/pubmed/12555134
    Wang et al. are able to explain the b-crystallin effect in cardiomyopathy satisfactorily without involving reduced glutathione. Elevated GSH may just be a side effect of excessive desmin; the cell's effort to compensate, perhaps, or a harmless side effect. The fact that Benjamin et al. found that enzymes (including GPx) were elevated suggests the former. I don't understand why Benjamin ignores desmin. If you factor it in, it can explain everything. The cell makes more GSH because it is already struggling; and the upregulation of GPx and glutathione reductase means that there is lots of oxidised GSSG there as well - which makes nonsense of the reductive stress claim if you think about it. In any case, any role of GSH in heart disease is irrelevant to people lacking the b-crystallin, desmin mutation. To me Benjamin's experiment (as reported here and in the abstract) does not prove his thesis, even on its own terms.

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