Antioxidants, such as vitamins C and E, can offer healthful benefits by protecting against damaging free radicals, but a new study in the journal Cell shows that balance is vitally important, and an overload of natural antioxidants can lead the heart to failure. Researcher Ivor Benjamin, from the University of Utah, said that the dark side of antioxidants had not previously been explored in any detail. "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," he noted. Reductants, or antioxidants, are elements or compounds that easily give up an electron to become "oxidized."
In the new 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 showed that mice with one of the mutant genes 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 results took Benjamin by surprise. He 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.
The results 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 concluded.
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Source: University of Utah
