title: Chronic depletion of glutathione exacerbates ventricular remodelling and dysfunction in the pressure-overloaded heart.
abstract: OBJECTIVE
  Chronic depletion of myocardial glutathione (GSH) may play a role in cardiac remodelling and dysfunction. This study examined the relationship between chronic GSH depletion and cardiac failure induced by pressure overload in mice lacking the modifier subunit (GCLM) of glutamate-cysteine ligase, the rate-limiting enzyme for GSH synthesis. In addition, we examined the association between idiopathic dilated cardiomyopathy (DCM) in humans and -588C/T polymorphism of the GCLM gene, which reduces plasma levels of GSH.
  
  
  RESULTS
  Pressure overload in mice was created by transverse aortic constriction (TAC). Myocardial GSH levels after TAC in GCLM(-/-) mice were 31% of those in GCLM(+/+) mice. TAC resulted in greater heart and lung-weight-to-body-weight ratios, greater dilation and dysfunction of left ventricle, more extensive myocardial fibrosis, and worse survival in GCLM(-/-) than GCLM(+/+) mice. Supplementation of GSH diethyl ester reversed the left-ventricular dilation and contractile dysfunction and the increased myocardial fibrosis after TAC in GCLM(-/-) mice. The prevalence of -588T polymorphism of the GCLM gene was significantly higher in DCM patients (n = 205) than in age- and sex-matched control subjects (n = 253) (36 vs. 19%, respectively, P < 0.001). The -588T polymorphism increased the risk of DCM that was independent of age, diabetes, and systolic blood pressure (OR 3.13, 95% CI: 2.28-4.44; P < 0.0001).
  
  
  CONCLUSIONS
  Chronic depletion of GSH exacerbates remodelling and dysfunction in the pressure-overloaded heart. The clinical relevance of this mouse model is supported by a significant association between -588T polymorphism of the GCLM gene and patients with DCM.
authors.affiliation: Department of Internal Medicine II,  University of Yamanashi, Faculty of Medicine, 1110 Shimokato, Chuo, Yamanashi 409-3898,  Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Saito
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fujioka
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Jun-ei
authors.initials: JE
authors.lastname: Obata
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kawabata
authors.forename: Hideto
authors.initials: H
authors.lastname: Mishina
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kugiyama
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D004452:Echocardiography; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000502:physiology*; D005978:Glutathione / Q000502:physiology*; D006439:Hemodynamics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000209:etiology*; D020257:Ventricular Remodeling
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D002118:Calcium