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Chronic depletion of glutathione exacerbates ventricular remodelling and dysfunction in the pressure-overloaded heart

Yosuke Watanabe1, Kazuhiro Watanabe, Tsuyoshi Kobayashi

  • 1Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.

Cardiovascular Research
|November 7, 2012
PubMed

Insights

Chronic glutathione (GSH) depletion worsens heart failure in mice. A genetic link between reduced GSH synthesis and human dilated cardiomyopathy (DCM) was also found, suggesting GSH

Area of Science:

  • Cardiology
  • Biochemistry
  • Genetics

Background:

  • Chronic depletion of myocardial glutathione (GSH) is implicated in cardiac remodeling and dysfunction.
  • Glutamate-cysteine ligase modifier subunit (GCLM) is crucial for GSH synthesis.
  • Reduced GSH levels are linked to cardiac pathology.

Purpose of the Study:

  • To investigate the role of chronic GSH depletion in pressure overload-induced cardiac failure using GCLM-deficient mice.
  • To explore the association between a GCLM gene polymorphism and idiopathic dilated cardiomyopathy (DCM) in humans.

Main Methods:

  • Created pressure overload in mice via transverse aortic constriction (TAC).
  • Assessed cardiac function, fibrosis, and survival in GCLM knockout and wild-type mice.
  • Administered GSH diethyl ester to GCLM knockout mice post-TAC.
  • Genotyped patients with DCM and control subjects for the GCLM -588C/T polymorphism.

Main Results:

  • GCLM(-/-) mice exhibited exacerbated cardiac dysfunction, fibrosis, and mortality after TAC compared to GCLM(+/+) mice.
  • GSH diethyl ester supplementation ameliorated cardiac damage in GCLM(-/-) mice.
  • The -588T polymorphism of the GCLM gene was significantly more prevalent in DCM patients (36%) than controls (19%).
  • The -588T polymorphism was an independent risk factor for DCM (OR 3.13).

Conclusions:

  • Chronic GSH depletion exacerbates cardiac remodeling and dysfunction under pressure overload.
  • The GCLM gene polymorphism (-588T) is associated with an increased risk of DCM in humans.
  • These findings highlight the critical role of GSH in maintaining cardiac health and suggest a genetic predisposition to DCM.
Abstract

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