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

作者：Watanabe Yosuke; Watanabe Kazuhiro; Kobayashi Tsuyoshi; Saito Yukio; Fujioka Daisuke; Nakamura Takamitsu; Obata Jun ei; Kawabata Kenichi; Mishina Hideto; Kugiyama Kiyotaka^*

来源：Cardiovascular Research, 2013, 97(2): 282-292.

DOI：10.1093/cvr/cvs333

• Cardiomyopathy
• Fibrosis
• Gene polymorphisms
• Heart failure
• Oxygen radicals

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 glutamatecysteine 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. %26lt;br%26gt;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: 2.284.44; P 0.0001). %26lt;br%26gt;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.

• 出版日期2013-2