title: Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice.
abstract: 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.
authors: Center for Cardiovascular Translational Biomedicine, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Namakkal S
authors: NS
authors: Rajasekaran
authors: Patrice
authors: P
authors: Connell
authors: Elisabeth S
authors: ES
authors: Christians
authors: Liang-Jun
authors: LJ
authors: Yan
authors: Ryan P
authors: RP
authors: Taylor
authors: András
authors: A
authors: Orosz
authors: Xiu Q
authors: XQ
authors: Zhang
authors: Tamara J
authors: TJ
authors: Stevenson
authors: Ronald M
authors: RM
authors: Peshock
authors: Jane A
authors: JA
authors: Leopold
authors: William H
authors: WH
authors: Barry
authors: Joseph
authors: J
authors: Loscalzo
authors: Shannon J
authors: SJ
authors: Odelberg
authors: Ivor J
authors: IJ
authors: Benjamin
mesh_terms: 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
chemical_list: D011506:Proteins; D038203:alpha-Crystallin B Chain; D001120:Arginine; D005954:Glucosephosphate Dehydrogenase; D005978:Glutathione; D005998:Glycine
references: N Engl J Med. 2000 Mar 16;342(11):770-80
references: 10717012
references: J Cell Physiol. 2000 Apr;183(1):100-7
references: 10699971
references: Proc Natl Acad Sci U S A. 1982 Nov;79(22):6866-70
references: 6294660
references: Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3461-6
references: 16877416
references: Circ Res. 2001 Jul 6;89(1):84-91
references: 11440982
references: Arch Biochem Biophys. 1999 Oct 15;370(2):236-9
references: 10510282
references: FASEB J. 2001 Aug;15(10):1771-3
references: 11481225
references: Nature. 1992 Jan 2;355(6355):33-45
references: 1731198
references: EMBO J. 1996 Jun 3;15(11):2695-706
references: 8654367
references: Genes Dev. 1998 Dec 15;12(24):3788-96
references: 9869631
references: Biochem Biophys Res Commun. 2006 Aug 11;346(4):1115-7
references: 16793013
references: EMBO J. 2002 Oct 1;21(19):5164-72
references: 12356732
references: Annu Rev Pharmacol Toxicol. 2006;46:215-34
references: 16402904
references: Antioxid Redox Signal. 2006 Jul-Aug;8(7-8):1315-27
references: 16910779
references: J Clin Invest. 2005 Mar;115(3):495-9
references: 15765130
references: Biochem J. 2005 Oct 15;391(Pt 2):335-41
references: 15952936
references: Am J Hum Genet. 1999 Mar;64(3):685-90
references: 10053001
references: J Card Fail. 2005 Aug;11(6):473-80
references: 16105639
references: Exp Cell Res. 1999 Feb 25;247(1):61-78
references: 10047448
references: Nat Genet. 1998 Aug;19(4):402-3
references: 9697706
references: J Mol Cell Cardiol. 1998 Apr;30(4):811-8
references: 9602430
references: Brain. 2004 Apr;127(Pt 4):723-34
references: 14724127
references: Nat Med. 2007 Feb;13(2):189-97
references: 17273168
references: FASEB J. 1994 Feb;8(2):174-81
references: 8119488
references: J Biol Chem. 1999 Aug 20;274(34):24137-41
references: 10446186
references: Brain. 2004 Feb;127(Pt 2):439-51
references: 14711882
references: Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10132-6
references: 15220483
references: Physiol Rev. 1979 Jul;59(3):527-605
references: 37532
references: Proc Natl Acad Sci U S A. 1991 May 1;88(9):3652-6
references: 2023914
references: Crit Care Med. 2002 Jan;30(1 Supp):S43-S50
references: 11839944
references: Cell. 2006 May 5;125(3):443-51
references: 16678092
references: J Cell Biol. 1995 Jul;130(1):41-9
references: 7790376
references: Nat Genet. 1998 Sep;20(1):92-5
references: 9731540
references: Rev Neurol (Paris). 1978 Jun-Jul;134(6-7):411-25
references: 570292
references: Mol Microbiol. 2002 Nov;46(3):869-78
references: 12410842
references: Anal Biochem. 1980 Jul 15;106(1):207-12
references: 7416462
references: J Biol Chem. 1999 Nov 19;274(47):33235-43
references: 10559197
references: J Mol Cell Cardiol. 2006 Aug;41(2):340-9
references: 16828794
references: J Cell Biol. 1998 Dec 28;143(7):1883-98
references: 9864362
references: Cell Stress Chaperones. 2003 Spring;8(1):53-61
references: 12820654
references: Proc Natl Acad Sci U S A. 1999 May 25;96(11):6137-42
references: 10339554
references: FEBS Lett. 2005 Jul 4;579(17):3777-82
references: 15978589
references: J Biol Chem. 2006 Feb 10;281(6):3382-8
references: 16354666