title: Glucose-6-phosphate dehydrogenase modulates cytosolic redox status and contractile phenotype in adult cardiomyocytes.
abstract: Reactive oxygen species (ROS)-mediated cell injury contributes to the pathophysiology of cardiovascular disease and myocardial dysfunction. Protection against ROS requires maintenance of endogenous thiol pools, most importantly, reduced glutathione (GSH), by NADPH. In cardiomyocytes, GSH resides in two separate cellular compartments: the mitochondria and cytosol. Although mitochondrial GSH is maintained largely by transhydrogenase and isocitrate dehydrogenase, the mechanisms responsible for sustaining cytosolic GSH remain unclear. Glucose-6-phosphate dehydrogenase (G6PD) functions as the first and rate-limiting enzyme in the pentose phosphate pathway, responsible for the generation of NADPH in a reaction coupled to the de novo production of cellular ribose. We hypothesized that G6PD is required to maintain cytosolic GSH levels and protect against ROS injury in cardiomyocytes. We found that in adult cardiomyocytes, G6PD activity is rapidly increased in response to cellular oxidative stress, with translocation of G6PD to the cell membrane. Furthermore, inhibition of G6PD depletes cytosolic GSH levels and subsequently results in cardiomyocyte contractile dysfunction through dysregulation of calcium homeostasis. Cardiomyocyte dysfunction was reversed through treatment with either a thiol-repleting agent (L-2-oxothiazolidine-4-carboxylic acid) or antioxidant treatment (Eukarion-134), but not with exogenous ribose. Finally, in a murine model of G6PD deficiency, we demonstrate the development of in vivo adverse structural remodeling and impaired contractile function over time. We, therefore, conclude that G6PD is a critical cytosolic antioxidant enzyme, essential for maintenance of cytosolic redox status in adult cardiomyocytes. Deficiency of G6PD may contribute to cardiac dysfunction through increased susceptibility to free radical injury and impairment of intracellular calcium transport. The full text of this article is available online at http://www.circresaha.org.
authors.affiliation: Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, Mass, USA.
authors.forename: Mohit
authors.initials: M
authors.lastname: Jain
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Brenner
authors.forename: Lei
authors.initials: L
authors.lastname: Cui
authors.forename: Chee Chew
authors.initials: CC
authors.lastname: Lim
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: David R
authors.initials: DR
authors.lastname: Pimentel
authors.forename: Stanley
authors.initials: S
authors.lastname: Koh
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
authors.forename: Jane A
authors.initials: JA
authors.lastname: Leopold
authors.forename: Diane E
authors.initials: DE
authors.lastname: Handy
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
authors.forename: Carl S
authors.initials: CS
authors.lastname: Apstein
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism*; D004195:Disease Models, Animal; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010641:Phenotype; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013347:Subcellular Fractions / Q000737:chemistry
chemical_list: D016877:Oxidants; D017382:Reactive Oxygen Species; D005954:Glucosephosphate Dehydrogenase; D002118:Calcium