Leukocyte-Derived Myeloperoxidase Amplifies High-Glucose—Induced Endothelial Dysfunction Through Interaction With High-Glucose—Stimulated, Vascular Non—Leukocyte-Derived Reactive Oxygen Species

Abstract

Vascular non–leukocyte-derived reactive oxygen species (ROS), such as superoxide and hydrogen peroxide (H2O2), have emerged as important molecules in diabetic endothelial dysfunction. In addition, leukocyte-derived myeloperoxidase (MPO) has been implicated in vascular injury, and its injury response is H2O2 dependent. It is well known that MPO can use leukocyte-derived H2O2; however, it is unknown whether the vascular-bound MPO can use high-glucose–stimulated, vascular non–leukocyte-derived H2O2 to induce diabetic endothelial dysfunction. In the present study, we demonstrated that MPO activity is increased in vessels from diabetic rats. In high-glucose–incubated rat aortas and in carotid arteries from rats with acute hyperglycemia, vascular-bound MPO utilized high-glucose–stimulated H2O2 to amplify the ROS-induced impairment of endothelium-dependent relaxation via reduction of nitric oxide bioavailability. Hypochlorous acid (HOCL)-modified LDL, a specific biomarker for the MPO/HOCL/chlorinating species pathway, was detected in LDL- and MPO-bound vessels with high-glucose–stimulated H2O2. The results suggest that vascular-bound MPO could use high-glucose–stimulated H2O2 to amplify high-glucose–induced injury in the vascular wall. MPO/H2O2/HOCL/chlorinating species may represent an important pathway in diabetes complications and a new mechanism in phagocyte- and systemic infection–induced exacerbation of diabetic vascular diseases.