Reductive stress, like its counterpart oxidative stress, can induce cardiomyopathy. August 16th, 2007

August 16th, 2007 By Farhad Abtahian, M.D. Ph.D. [mailto:fabtahian@partners.org]

Reductive stress, the counterpart of the more ubiquitous oxidative stress, contributes to cardiomyopathy according to a fascinating new study that for the first time links reductive stress to human disease. Oxidative stress (i.e. excessive production of reactive oxygen species) has clearly been linked to a number of disease states including heart failure. Rajasekaran et al. demonstrate that excessive levels of reducing equivalents (or reductive stress) may underlie the pathogenesis of a specific type of protein aggregation cardiomyopathy caused by mutations in the alphaB-crystallin gene.

Mutations in the alphaB-crystallin (CryAB) gene (and also desmin) result in a protein aggregation cardiomyopathy in humans. Cardiac tissue specific expression of mutant forms of CryAB (carrying the disease causing mutation) in mice recapitulates the cardiomyopathy seen in humans with protein aggregation leading to progressive heart failure, cardiac hypertrophy and eventual cardiac remodeling and dilation. Over expression of mutant CryAB activates the heat shock protein (HSP) stress pathway (also known to be activated in human heart failure) and results in the up-regulation of anti-oxidative pathways with enhanced activity of both glutathione peroxidase and catalase activity. Likely as a consequence of the above two findings, there is a shift in the oxidative-reduction balance with an increase in the amount of reducing equivalents relative to oxidizing equivalents as measured by the relative amounts of reduced glutathione (GSH) relative to oxidized glutathione (GSSG).

GSH is produced by the reduction of GSSG via the oxidation of NADPH by the enzyme GSH-reductase. NADPH is produced by the enzyme glucose-6-phosphate dehydrogenase (G6PD), which is expressed at significantly higher levels in the hearts of mice expressing the mutant form of CryAB. Transgenic mice expressing mutant CryAB were crossed with mice maintaining as little as 20% of the normal levels of G6PD activity. The intercrossed mice had significantly less protein aggregation and cardiomyopathy, results that strongly suggest a causal link between increased G6PD levels (and hence reductive stress) and cardiomyopathy.

The findings of Rajasekaran et al. pinpoint reductive stress, for the first time, as the metabolic disturbance responsible for the pathogenesis of a human disease. This raises the possibility that reductive stress may be responsible for diseases other than protein aggregation cardiomyopathy. As an accompanying editorial notes, the elegant work of Rajasekaran et al. may also explain the disappointing results of antioxidant therapy in heart failure and suggests that treatment of heart failure will require balancing both oxidative and reductive stress.

Rajasekaran NS, Connell P, Christians ES, Yan J-L, Taylor RP, Orosz A, Zhang XQ, Stevenson TJ, Peshock RM, Leopold JA, Barry WH, Loscalzo J, Odelberg SJ, and Benjamin IJ. Human alphaB-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice. Cell 2007 Aug 10; 130(3):427.