Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
Cardiovasc Res. 2013 Feb 1;97(2):282-92. doi: 10.1093/cvr/cvs333. Epub 2012 Nov 5.
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.
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).
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.
心肌谷胱甘肽（GSH）的慢性耗竭可能在心脏重塑和功能障碍中发挥作用。本研究探讨了在缺乏谷氨酸半胱氨酸连接酶修饰亚基（GCLM）的小鼠中，GSH 合成限速酶，慢性 GSH 耗竭与压力超负荷诱导的心力衰竭之间的关系。此外，我们还研究了人类特发性扩张型心肌病（DCM）与 GCLM 基因-588C/T 多态性之间的关联，该多态性降低了 GSH 的血浆水平。
通过横主动脉缩窄（TAC）在小鼠中建立压力超负荷。TAC 后 GCLM（-/-）小鼠心肌 GSH 水平为 GCLM（+/+）小鼠的 31%。TAC 导致 GCLM（-/-）小鼠的心脏和肺重量与体重比、左心室扩张和功能障碍、心肌纤维化更广泛以及存活率更差。GSH 二乙酯的补充逆转了 TAC 后 GCLM（-/-）小鼠的左心室扩张和收缩功能障碍以及心肌纤维化的增加。GCLM 基因-588T 多态性在 DCM 患者（n=205）中的发生率明显高于年龄和性别匹配的对照组（n=253）（分别为 36%和 19%，P<0.001）。-588T 多态性增加了 DCM 的风险，且独立于年龄、糖尿病和收缩压（OR 3.13，95%CI：2.28-4.44；P<0.0001）。
GSH 的慢性耗竭加剧了压力超负荷心脏的重塑和功能障碍。GCLM 基因-588T 多态性与 DCM 患者之间存在显著关联，支持了该小鼠模型的临床相关性。
