Glutamine enhances endothelial cell survival and vasodilation by increasing glutathione to reduce oxidative stress

Cardiovascular disease is exacerbated by diabetes through hyperglycemia-induced endothelial dysfunction, which arises from oxidative stress. Glutamine is postulated to decrease oxidative stress; however, its effect on endothelial dysfunction in hyperglycemia is unknown. Therefore, we investigated how glutamine affects endothelial function in normal and high glucose. Human coronary artery endothelial cells were treated with 0, 0.5, or 2 mM glutamine in 5.5 or 15 mM glucose for 24 h. We then assessed cell proliferation, oxidative stress, cell survival, and endothelial nitric oxide synthase (eNOS) activity. Our data showed that independent of glucose concentration, glutamine increased proliferation by up to 3.5-fold. Furthermore, glutamine metabolism through glutaminase-1 reduced oxidative stress and cell death by up to 70% and 94%, respectively, by doubling glutathione and NADPH. Glutamine also increased ex vivo vasodilation in isolated murine carotid arteries without altering eNOS activity or nitric oxide in vitro, suggesting that the enhanced vasodilation results from reduced oxidative stress. These findings indicate that glutamine mitigates endothelial cell oxidative stress by enhancing reducing capacity, which may protect against diabetic cardiovascular disease.