Gain and Loss of Function for Glutathione Synthesis

Abstract

Objective— Glutamate-cysteine ligase (GCL) is the rate-limiting step in glutathione synthesis. The enzyme is a heterodimer composed of a catalytic subunit, GCLC, and a modifier subunit, GCLM. We generated apolipoprotein E (apoE)−/− mice deficient in GCLM ( apoE −/−/ Gclm −/−) and transgenic mice that overexpress GCLC specifically in macrophages ( apoE −/−/ Gclc-Tg ) to test the hypothesis that significantly altering the availability of glutathione has a measurable impact on both the initiation and progression of atherosclerosis. Methods and Results— Atherosclerotic plaque size and composition were measured in the innominate artery in chow-fed male and female mice at 20, 30, 40, and 50 weeks of age and in the aortic sinus at 40 and 50 weeks of age. The apoE −/−/ Gclm −/− mice more rapidly developed complex lesions, whereas the apoE −/−/ Gclc-Tg mice had reduced lesion development compared with the littermate apoE −/− control mice. Transplantation of bone marrow from the apoE −/−/ Gclm −/− and apoE −/−/ Gclc-Tg mice into apoE −/− mice with established lesions also stimulated or inhibited further lesion development at 30 weeks posttransplant. Conclusion— Gain and loss of function in the capacity to synthesize glutathione especially in macrophages has reciprocal effects on the initiation and progression of atherosclerosis at multiple sites in apoE−/− mice.