Reductive stress: linking heat shock protein 27, glutathione, and cardiomyopathy?

Normal cellular functions essentially depend on a balanced redox environment. Free radicals and nonradical oxidants can shift the redox balance toward a more “oxidized” state, which is counteracted by the intracellular antioxidant defense systems. These include the enzymes superoxide dismutase and catalase, as well as the thiol-reducing systems (glutathione, glutaredoxin, and thioredoxin). Glutathione is the most abundant intracellular low molecular weight thiol existing predominantly in the thiol-reduced form (GSH), whereas the disulfide-oxidized form (GSSG) represents 2%. Glutathione regulates numerous cellular functions; GSH as an antioxidant reduces hydrogen peroxide and peroxynitrite directly and indirectly with the help of glutathione peroxidase, detoxifies electrophiles, modulates the reversible oxidation and reduction of protein thiols, and is critically involved in the regulation of enzymes, transcription factors, and signal transduction.1 Loss of glutathione or disturbance of the GSH/GSSG redox potential causes cellular dysfunction. Multiple diseases, including cardiovascular diseases, are associated with the depletion of glutathione and a shift toward more oxidized GSH/GSSG redox potential. Restoring the GSH levels by substituting the glutathione precursor N-acetylcysteine or overexpressing glutathione peroxidase prevents cardiac dysfunction.2,3 However, little is known about the consequences of a more reductive redox state for cardiac function. Rajasekaran et al4 first reported about “reductive stress” in mice expressing the human mutant B-crystallin protein. These mice developed enhanced activity of glucose-6-phosphate dehydrogenase with increased production of NADPH and higher levels of GSH resulting in protein aggregation and cardiomyopathy. The human mutant B-crystallin protein further induced expression of heat shock proteins (Hsps), in particular, Hsp25, and glutathione peroxidase, and decreased myocardial levels of reactive oxygen species. Hsps are upregulated under oxidative stress and protect against reactive oxygen species; they have also been implicated to influence glutathione metabolism.5,6 In the present issue of Hypertension, Zhang et al7 report that cardiomyocyte-specific overexpression of Hsp27 induces