Involvement of Reductive Stress in the Cardiomyopathy in Transgenic Mice With Cardiac-Specific Overexpression of Heat Shock Protein 27

Zhang, Xia; Min, Xiaoyan; Li, Chuanfu; Benjamin, Ivor J.; Qian, Bo; Zhang, Xiaojin; Ding, Zhengnian; Gao, Xiang; Yao, Yuzhen; Ma, Yujie; Cheng, Yunling; Liu, Li

doi:10.1161/hypertensionaha.109.147066

Cited by 101 publications

(96 citation statements)

References 27 publications

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“…4). Although earlier the deleterious effects of reductive stress have been explored in both unicellular eukaryotic and mammalian cells (49,99,118,134), there remains a paucity of robust experimental models beyond the examples described herein (99,135). We embrace the widespread use of redox biosensors, such as roGFPs, Trx1, and Trx2, which are well suited to independently assess GSH depletion, after induction of either H 2 O 2 or superoxide production at subcellular levels.…”

Section: Discussionmentioning

confidence: 99%

“…Although HSPB1 influences the intracellular redox homeostasis by upholding reduced GSH and decreasing intracellular iron levels (11), direct physiological evidence for such proreducing properties remain speculative. To test the hypothesis that HSPB1 overexpression is necessary and sufficient to generate a proreducing state, Zhang and coworkers generated TG mice harboring cardiac-specific overexpression of HSPB1 in TG mice (135). Among the TG lines, mild (*2-fold) to moderate (*7-fold) overexpression (OE) of HSPB1 was found to have no effect on cardiac growth, whereas high (*15-fold) HSPB1 OE caused spontaneous hypertrophy, which progressed into overt heart failure by 43 weeks (135).…”

Section: A Genetic Model Of Human Hspb1 Overexpression Mimics Reductimentioning

confidence: 99%

“…To test the hypothesis that HSPB1 overexpression is necessary and sufficient to generate a proreducing state, Zhang and coworkers generated TG mice harboring cardiac-specific overexpression of HSPB1 in TG mice (135). Among the TG lines, mild (*2-fold) to moderate (*7-fold) overexpression (OE) of HSPB1 was found to have no effect on cardiac growth, whereas high (*15-fold) HSPB1 OE caused spontaneous hypertrophy, which progressed into overt heart failure by 43 weeks (135). TG mice with high HSPB1 OE exhibited significantly increased GSH and GSH/GSSG ratio, which correlated reciprocally with a decrease in protein carbonylation and with elevated GPx, consistent with maintaining GSH in the reduced state and a general shift in the redox imbalance toward the reductive spectrum.…”

Section: A Genetic Model Of Human Hspb1 Overexpression Mimics Reductimentioning

confidence: 99%

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Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease

Brewer

Mustafi

Murray

et al. 2013

Antioxidants & Redox Signaling

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Significance: Aerobic organisms must exist between the dueling biological metabolic processes for energy and respiration and the obligatory generation of reactive oxygen species (ROS) whose deleterious consequences can reduce survival. Wide fluctuations in harmful ROS generation are circumvented by endogenous countermeasures (i.e., enzymatic and nonenzymatic antioxidants systems) whose capacity decline with aging and are enhanced by disease states. Recent Advances: Substantial efforts on the cellular and molecular underpinnings of oxidative stress has been complemented recently by the discovery that reductive stress similarly predisposes to inheritable cardiomyopathy, firmly establishing that the biological extremes of the redox spectrum play essential roles in disease pathogenesis. Critical Issues: Because antioxidants by nutritional or pharmacological supplement to prevent or mitigate disease states have been largely disappointing, we hypothesize that lack of efficacy of antioxidants might be related to adverse outcomes in responders at the reductive end of the redox spectrum. As emerging concepts, such as reductive, as opposed, oxidative stress are further explored, there is an urgent and critical gap for biochemical phenotyping to guide the targeted clinical applications of therapeutic interventions. Future Directions: New approaches are vitally needed for characterizing redox states with the long-term goal to noninvasively assess distinct clinical states (e.g., presymptomatic, end-stage) with the diagnostic accuracy to guide personalized medicine.

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Section: Discussionmentioning

confidence: 99%

Section: A Genetic Model Of Human Hspb1 Overexpression Mimics Reductimentioning

confidence: 99%

Section: A Genetic Model Of Human Hspb1 Overexpression Mimics Reductimentioning

confidence: 99%

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Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease

Brewer

Mustafi

Murray

et al. 2013

Antioxidants & Redox Signaling

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“…Furthermore, Hsp27 has been demonstrated to play an important role in regulating intracellular redox homeostasis and anti-apoptosis (Arrigo et al 2005). We speculate that increased expression of Hsp27 in the lower concentration of F − exposure might be due to its reductive stress-associated cardiomyopathy (Zhang et al 2010). Besides, decreased expression of Hsp27 in the higher concentration of F − might be due to enhanced apoptotic stimulus in the rat heart.…”

Section: Resultsmentioning

confidence: 88%

Differential expression of myocardial heat shock proteins in rats acutely exposed to fluoride

Panneerselvam

Raghunath

2017

Cell Stress and Chaperones

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Acute fluoride (F − ) toxicity is known to cause severe cardiac complications and leads to sudden heart failure. Previously, we reported that increased myocardial oxidative damage, apoptosis, altered cytoskeleton and AMPK signaling proteins associated with energy deprivation in acute F − induced cardiac dysfunction. The present study was aimed to decipher the status of myocardial heat shock proteins (HspsHsp27, Hsp32, Hsp40, Hsp60, Hsp70, Hsp90) and heat shock transcription factor 1 (Hsf1) in acute F − -intoxicated rats. In order to study the expression of myocardial Hsps, male Wistar rats were treated with single oral doses of 45 and 90 mg/kg F − for 24 h. The expression levels of myocardial Hsps were determined using RT-PCR, western blotting, and immunohistochemical studies. Acute F − -intoxicated rats showed elevated levels of both the transcripts and protein expression of Hsf1, Hsp27, Hsp32, Hsp60, and Hsp70 when compared to control. In addition, the expression levels of Hsp40 and Hsp90 were significantly declined in a dosedependent fashion in F − -treated animals. Our result suggests that differential expression of Hsps in the rat myocardium could serve as a balance between pro-survival and death signal during acute F − -induced heart failure.

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“…Elevated GSH and glutathione peroxidase activity decrease levels of reactive oxygen species and might alter S-glutathionylation of several enzymes, transcription factors, and signaling proteins. By partly inhibiting glutathi- one peroxidase activity to the level of wild-type animals, Zhang et al 7 were able to prevent cardiomyopathy in Hsp27-overexpressing animals, suggesting that Hsp27-induced cardiomyopathy is at least in part mediated by elevated glutathione peroxidase activity. Cardiac structure and function were neither altered in transgenic mice with lower levels of Hsp27 overexpression in the present study nor in mice with overexpression of glutathione peroxidase, which may be explained by the fact that glutathione peroxidase activity was only mildly increased.…”

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confidence: 99%

Reductive Stress

Bauersachs

Widder

2010

Hypertension

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N ormal 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 Ͻ2%. 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 al 4 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 al 7 report that cardiomyocyte-specific overexpression of Hsp27 induces reductive stress in the heart. In particular, mice expressing high levels of Hsp27 displayed increased myocardial glutathione peroxidase expression and activity, GSH, and GSH/ GSSG ratio and decreased reactive oxygen species levels, resulting in cardiac hypertrophy, dysfunction, and reduced lifespan (Figure). Elevated GSH and glutathione peroxidase activity decrease levels of reactive oxygen species and might alter S-glutathionylation of several enzymes, transcription factors, and signaling proteins. By partly inhibiting glutathiThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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Involvement of Reductive Stress in the Cardiomyopathy in Transgenic Mice With Cardiac-Specific Overexpression of Heat Shock Protein 27

Cited by 101 publications

References 27 publications

Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease

Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease

Differential expression of myocardial heat shock proteins in rats acutely exposed to fluoride

Reductive Stress

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