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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...

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These data demonstrate for the first time that the overexpression of HSPA12B attenuates cardiac dysfunction and remodelling after MI. This action of HSPA12B was mediated, at least in part, by prevention of cardiomyocyte apoptosis and promotion of myocardial angiogenesis via an eNOS-dependent mechanism. HSPA12B could be a novel target for the management of patients with post-MI cardiac dysfunction and remodelling.

these results suggest that HSPA12B plays an important role in the attenuation of endotoxin-induced cardiac dysfunction and that the mechanisms involve the preserved activation of PI3K/Akt signalling, resulting in attenuation of LPS-increased expression of VCAM-1/ICAM-1 and leucocyte infiltration into the myocardium.

Our data suggest that LA stimulates neurite outgrowth through the activation of ERK signaling, an effect mediated through a ROS-dependent mechanism. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.

Cardiac dysfunction is a major consequence of septic shock and may be responsible for the high mortality of sepsis. We have reported that transgenic mice with cardiac-specific overexpression of heat shock protein 27 (Hsp27 Tg) exhibited the protection against doxorubicin-induced cardiac dysfunction. We hypothesized that overexpression of Hsp27 will attenuate cardiac dysfunction during endotoxemia. Hsp27 Tg and age-matched wild-type (WT) mice were injected with LPS. Cardiac function was evaluated by echocardiography, survival rate was carefully monitored, and activities of signaling pathways were determined by immunoblot. LPS administration significantly decreased cardiac function in WT mice. In Hsp27 Tg mice, LPS-induced cardiac dysfunction was significantly attenuated as evidenced by increased ejection fraction (27.3%) and fractional shortening (37.1%), respectively, compared with LPS-treated WT mice. Heat shock protein 27 Tg mice were more resistant to LPS-induced mortality than WT. The levels of phospho-Akt and phospho-glycogen synthase kinase 3beta (phospho-GSK-3beta) in the myocardium were significantly increased in Hsp27 Tg mice compared with WT after LPS administration. Nuclear factor kappaB-binding activity was significantly decreased in Hsp27 Tg mice compared with WT mice after LPS challenge. Similar results were observed in in vitro studies using Hsp27-transfected rat cardiomyoblasts. Importantly, phosphoinositide 3-kinase inhibition abolished the protective effect of Hsp27 in LPS-induced cardiac dysfunction and mortality of endotoxemia. Our results suggest that Hsp27 plays an important role in attenuation of cardiac dysfunction and mortality in endotoxemia and that the mechanisms of the protection may involve activation of the PI3K/Akt signaling pathway.

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