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Abstract-Oxidative stress plays an important role in cardiac diseases, which has been well demonstrated, whereas the role of reductive stress has been poorly investigated. We and others have shown previously that heat shock protein 27 (Hsp27) plays a role as an antioxidant. To investigate whether overexpression of Hsp27 could lead to reductive stress and result in cardiomyopathy, we generated transgenic mice with different expression levels of Hsp27. We observed that transgenic mice with high levels of Hsp27 developed cardiomyopathy. The myopathic hearts were under reductive stress, which was evidenced by an increased ratio of reduced glutathione/oxidized glutathione and a decreased level of reactive oxygen species. In addition, upregulated glutathione peroxidase 1 and decreased iron content were revealed in the myopathic hearts. More importantly, inhibition of glutathione peroxidase 1 significantly attenuated the development of cardiomyopathy. The data indicate that the Hsp27-induced cardiomyopathy could be attributed to, at least in part, upregulation of glutathione peroxidase 1. Our findings suggest that reductive stress plays an important role in the development of cardiomyopathy and that Hsp27 may serve as a potential target for the treatment of patients with cardiomyopathy. (Hypertension. 2010;55:1412-1417.)Key Words: Hsp27 Ⅲ oxidation Ⅲ redox Ⅲ cardiomyopathy Ⅲ iron Ⅲ cardiac function O xido-redox homeostasis is essential for normal metabolism of cardiomyocytes. 1 Oxidative stress has been well demonstrated to play critical roles in the pathophysiology of many cardiac diseases, including hypertrophy, 2 cardiac ischemic injury, 3 and congestive heart failure. 4 "Reductive stress" is the counterpart of oxidative stress, which is defined as an abnormal increase of reducing equivalents, such as the elevated ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG). 5 Similar to oxidative stress, reductive stress has also been shown to have a deleterious effect in lower eukaryotes. 6,7 For example, in yeast with reductive stress, some proteins showed delayed folding, disordered transport, and failed oxidation and were aggregated. 7 In addition, reductive stress enhanced protein aggregation and reduced life span of yeast and Caenorhabditis elegans. 6 -10 More significantly, Rajasekaran et al 5 reported a striking discovery that reductive stress can cause cardiomyopathy by protein aggregation in R120G ␣B-crystalline transgenic (Tg) mice, which mimic the clinical manifestations, phenotypic heterogeneity, and late onset of clinical signs and symptoms observed in desmin-related myopathy patients. Desmin-related myopathy is a heterogeneous group of muscle disorders morphologically defined by intrasarcoplasmic aggregates of desmin. The authors found that the myopathic hearts were under reductive stress, and the hearts exhibited dramatically increased levels of heat shock protein (Hsp) 25, which were positively correlated with protein aggregation. 5 However, it is unclear whether the upregulated Hsp25 will cont...