Molecular Pathway Leads to Reductive Stress Heart Disease

Cardiovascular disease researchers have traced a molecular pathway that leads to the formation of excessive amounts of the antioxidant-reduced glutathione, which causes heart disease due to "reductive stress.”

Pathologically high levels of reduced glutathione are found in individuals that carry a mutant gene for the protein alpha B-crystallin. This protein serves as a molecular chaperone that modulates the three-dimensional folding of other proteins. When alpha B-crystallin fails to function, a multisystem, protein aggregation disease including cardiomyopathy is the result. The cardiomayopathy is due to elevated levels of reduced glutatione, which puts the heart muscle into a state of reductive stress. The myopathic heart shows an increased recycling of oxidized glutathione (GSSG) to reduced glutathione (GSH), which is due to the augmented expression and enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, and glutathione peroxidase.

To determine the molecular basis for this syndrome, investigators at the University of Utah (Salt Lake City, USA) genetically engineered a line of mice to lack the gene for alpha B-crystallin. These animals produced an overabundance of reduced glutathione due to elevated G6PD activity, and their hearts displayed the same characteristics as human hearts suffering from reductive stress. The investigators then crossed mice from this population with mice with wild-type alpha B-crystallin and lower than normal levels of G6PD activity. Results published in the August 10, 2007, issue of the journal Cell revealed that the offspring of this match did not suffer from reductive stress syndrome.

"Lowering the level of reduced glutathione dramatically changed the survival of these mice,” explained senior author Dr. Ivor J. Benjamin, professor of cardiology at the University of Utah. "Basically, we prevented them from getting heart failure. This field of medicine has not appreciated reductive stress and its influence on disease. 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. By lowering the levels of reduced glutathione without the altering the mutant gene encoding alpha B-crystallin, our study shows reductive stress can be addressed through new drugs that target the genetic pathway causing the problem.”


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