Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice.
The autosomal dominant mutation in the human alphaB-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.
Rajasekaran
Namakkal S
NS
Center for Cardiovascular Translational Biomedicine, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Connell
Patrice
P
Christians
Elisabeth S
ES
Yan
Liang-Jun
LJ
Taylor
Ryan P
RP
Orosz
András
A
Zhang
Xiu Q
XQ
Stevenson
Tamara J
TJ
Peshock
Ronald M
RM
Leopold
Jane A
JA
Barry
William H
WH
Loscalzo
Joseph
J
Odelberg
Shannon J
SJ
Benjamin
Ivor J
IJ
D000818:Animals; D001120:Arginine / Q000235:genetics; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005998:Glycine / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D011506:Proteins / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000235:genetics* / Q000502:physiology
D011506:Proteins; D038203:alpha-Crystallin B Chain; D001120:Arginine; D005954:Glucosephosphate Dehydrogenase; D005978:Glutathione; D005998:Glycine
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