Human αB-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice

Namakkal S. Rajasekaran; Patrice Connell; Elisabeth S. Christians; Liang Jun Yan; Ryan P. Taylor; András Orosz; Xiu Q. Zhang; Tamara J. Stevenson; Ronald M Peshock; Jane A. Leopold; William H. Barry; Joseph Loscalzo; Shannon J. Odelberg; Ivor J. Benjamin

doi:10.1016/j.cell.2007.06.044

Human αB-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice

Namakkal S. Rajasekaran, Patrice Connell, Elisabeth S. Christians, Liang Jun Yan, Ryan P. Taylor, András Orosz, Xiu Q. Zhang, Tamara J. Stevenson, Ronald M Peshock, Jane A. Leopold, William H. Barry, Joseph Loscalzo, Shannon J. Odelberg, Ivor J. Benjamin

Research output: Contribution to journal › Article › peer-review

384 Scopus citations

Abstract

The autosomal dominant mutation in the human αB-crystallin gene inducing a R120G amino acid exchange causes a multisystem, protein aggregation disease including cardiomyopathy. The pathogenesis of cardiomyopathy in this mutant (hR120GCryAB) is poorly understood. Here, we show that transgenic mice overexpressing cardiac-specific hR120GCryAB recapitulate the cardiomyopathy in humans and find that the mice are under reductive stress. The myopathic hearts show an increased recycling of oxidized glutathione (GSSG) to reduced glutathione (GSH), which is due to the augmented expression and enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, and glutathione peroxidase. The intercross of hR120GCryAB cardiomyopathic animals with mice with reduced G6PD levels rescues the progeny from cardiac hypertrophy and protein aggregation. These findings demonstrate that dysregulation of G6PD activity is necessary and sufficient for maladaptive reductive stress and suggest a novel therapeutic target for abrogating R120GCryAB cardiomyopathy and heart failure in humans.

Original language	English (US)
Pages (from-to)	427-439
Number of pages	13
Journal	Cell
Volume	130
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2007.06.044
State	Published - Aug 10 2007

Keywords

HUMDISEASE
SIGNALING

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2007.06.044

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Rajasekaran, N. S., Connell, P., Christians, E. S., Yan, L. J., Taylor, R. P., Orosz, A., Zhang, X. Q., Stevenson, T. J., Peshock, R. M., Leopold, J. A., Barry, W. H., Loscalzo, J., Odelberg, S. J., & Benjamin, I. J. (2007). Human αB-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice. Cell, 130(3), 427-439. https://doi.org/10.1016/j.cell.2007.06.044

Rajasekaran, NS, Connell, P, Christians, ES, Yan, LJ, Taylor, RP, Orosz, A, Zhang, XQ, Stevenson, TJ, Peshock, RM, Leopold, JA, Barry, WH, Loscalzo, J, Odelberg, SJ & Benjamin, IJ 2007, 'Human αB-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice', Cell, vol. 130, no. 3, pp. 427-439. https://doi.org/10.1016/j.cell.2007.06.044

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title = "Human αB-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice",

abstract = "The autosomal dominant mutation in the human αB-crystallin gene inducing a R120G amino acid exchange causes a multisystem, protein aggregation disease including cardiomyopathy. The pathogenesis of cardiomyopathy in this mutant (hR120GCryAB) is poorly understood. Here, we show that transgenic mice overexpressing cardiac-specific hR120GCryAB recapitulate the cardiomyopathy in humans and find that the mice are under reductive stress. The myopathic hearts show an increased recycling of oxidized glutathione (GSSG) to reduced glutathione (GSH), which is due to the augmented expression and enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, and glutathione peroxidase. The intercross of hR120GCryAB cardiomyopathic animals with mice with reduced G6PD levels rescues the progeny from cardiac hypertrophy and protein aggregation. These findings demonstrate that dysregulation of G6PD activity is necessary and sufficient for maladaptive reductive stress and suggest a novel therapeutic target for abrogating R120GCryAB cardiomyopathy and heart failure in humans.",

keywords = "HUMDISEASE, SIGNALING",

author = "Rajasekaran, {Namakkal S.} and Patrice Connell and Christians, {Elisabeth S.} and Yan, {Liang Jun} and Taylor, {Ryan P.} and Andr{\'a}s Orosz and Zhang, {Xiu Q.} and Stevenson, {Tamara J.} and Peshock, {Ronald M} and Leopold, {Jane A.} and Barry, {William H.} and Joseph Loscalzo and Odelberg, {Shannon J.} and Benjamin, {Ivor J.}",

note = "Funding Information: An award from NHLBI (5RO1 HL63874) and Christi T. Smith Foundation provided support for this work. We appreciate the helpful comments and suggestions from our colleagues Matthew A. Firpo, Joseph Prchal, James Kushner, and John R. Hoidal. We are indebted to Patti Larrabee for assistance with animal husbandry and James Richardson and John Shelton for critical technical assistance with immunohistochemistry during the initial phases of this work. Tandy Bales and Krista J. Boeger provided excellent editorial assistance during preparation of this manuscript. ",

year = "2007",

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doi = "10.1016/j.cell.2007.06.044",

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AU - Rajasekaran, Namakkal S.

AU - Connell, Patrice

AU - Christians, Elisabeth S.

AU - Yan, Liang Jun

AU - Taylor, Ryan P.

AU - Orosz, András

AU - Zhang, Xiu Q.

AU - Stevenson, Tamara J.

AU - Peshock, Ronald M

AU - Leopold, Jane A.

AU - Barry, William H.

AU - Loscalzo, Joseph

AU - Odelberg, Shannon J.

AU - Benjamin, Ivor J.

N1 - Funding Information: An award from NHLBI (5RO1 HL63874) and Christi T. Smith Foundation provided support for this work. We appreciate the helpful comments and suggestions from our colleagues Matthew A. Firpo, Joseph Prchal, James Kushner, and John R. Hoidal. We are indebted to Patti Larrabee for assistance with animal husbandry and James Richardson and John Shelton for critical technical assistance with immunohistochemistry during the initial phases of this work. Tandy Bales and Krista J. Boeger provided excellent editorial assistance during preparation of this manuscript.

PY - 2007/8/10

Y1 - 2007/8/10

N2 - The autosomal dominant mutation in the human αB-crystallin gene inducing a R120G amino acid exchange causes a multisystem, protein aggregation disease including cardiomyopathy. The pathogenesis of cardiomyopathy in this mutant (hR120GCryAB) is poorly understood. Here, we show that transgenic mice overexpressing cardiac-specific hR120GCryAB recapitulate the cardiomyopathy in humans and find that the mice are under reductive stress. The myopathic hearts show an increased recycling of oxidized glutathione (GSSG) to reduced glutathione (GSH), which is due to the augmented expression and enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, and glutathione peroxidase. The intercross of hR120GCryAB cardiomyopathic animals with mice with reduced G6PD levels rescues the progeny from cardiac hypertrophy and protein aggregation. These findings demonstrate that dysregulation of G6PD activity is necessary and sufficient for maladaptive reductive stress and suggest a novel therapeutic target for abrogating R120GCryAB cardiomyopathy and heart failure in humans.

AB - The autosomal dominant mutation in the human αB-crystallin gene inducing a R120G amino acid exchange causes a multisystem, protein aggregation disease including cardiomyopathy. The pathogenesis of cardiomyopathy in this mutant (hR120GCryAB) is poorly understood. Here, we show that transgenic mice overexpressing cardiac-specific hR120GCryAB recapitulate the cardiomyopathy in humans and find that the mice are under reductive stress. The myopathic hearts show an increased recycling of oxidized glutathione (GSSG) to reduced glutathione (GSH), which is due to the augmented expression and enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, and glutathione peroxidase. The intercross of hR120GCryAB cardiomyopathic animals with mice with reduced G6PD levels rescues the progeny from cardiac hypertrophy and protein aggregation. These findings demonstrate that dysregulation of G6PD activity is necessary and sufficient for maladaptive reductive stress and suggest a novel therapeutic target for abrogating R120GCryAB cardiomyopathy and heart failure in humans.

KW - HUMDISEASE

KW - SIGNALING

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ER -

Human αB-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice

Abstract

Keywords

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