title: Glucose 6-phosphate dehydrogenase deficiency increases redox stress and moderately accelerates the development of heart failure.
abstract: BACKGROUND
  Glucose 6-phosphate dehydrogenase (G6PD) is the most common deficient enzyme in the world. In failing hearts, G6PD is upregulated and generates reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is used by the glutathione pathway to remove reactive oxygen species but also as a substrate by reactive oxygen species-generating enzymes. Therefore, G6PD deficiency might prevent heart failure by decreasing NADPH and reactive oxygen species production.
  
  
  RESULTS
  This hypothesis was evaluated in a mouse model of human G6PD deficiency (G6PDX mice, ≈40% normal activity). Myocardial infarction with 3 months follow-up resulted in left ventricular dilation and dysfunction in both wild-type and G6PDX mice but significantly greater end diastolic volume and wall thinning in G6PDX mice. Similarly, pressure overload induced by transverse aortic constriction (TAC) for 6 weeks caused greater left ventricular dilation in G6PDX mice than wild-type mice. We further stressed transverse aortic constriction mice by feeding a high fructose diet to increase flux through G6PD and reactive oxygen species production and again observed worse left ventricular remodeling and a lower ejection fraction in G6PDX than wild-type mice. Tissue content of lipid peroxidation products was increased in G6PDX mice in response to infarction and aconitase activity was decreased with transverse aortic constriction, suggesting that G6PD deficiency increases myocardial oxidative stress and subsequent damage.
  
  
  CONCLUSIONS
  Contrary to our hypothesis, G6PD deficiency increased redox stress in response to infarction or pressure overload. However, we found only a modest acceleration of left ventricular remodeling, suggesting that, in individuals with G6PD deficiency and concurrent hypertension or myocardial infarction, the risk for developing heart failure is higher but limited by compensatory mechanisms.
authors.affiliation: Division of Cardiology and Department of Medicine, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Hecker
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lionetti
authors.forename: Rogerio F
authors.initials: RF
authors.lastname: Ribeiro
authors.forename: Sharad
authors.initials: S
authors.lastname: Rastogi
authors.forename: Bethany H
authors.initials: BH
authors.lastname: Brown
authors.forename: Kelly A
authors.initials: KA
authors.lastname: O'Connell
authors.forename: James W
authors.initials: JW
authors.lastname: Cox
authors.forename: Kadambari C
authors.initials: KC
authors.lastname: Shekar
authors.forename: Dionna M
authors.initials: DM
authors.lastname: Gamble
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.forename: Jane A
authors.initials: JA
authors.lastname: Leopold
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Gupte
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Recchia
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000150:complications* / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009206:Myocardium / Q000201:enzymology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D017382:Reactive Oxygen Species; D005954:Glucosephosphate Dehydrogenase