Gain and Loss of Function for Glutathione Synthesis Impact on Advanced Atherosclerosis in Apolipoprotein E-Deficient Mice

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. (Arterioscler Thromb Vasc Biol. 2011;31:2473-2482.)