title: 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 (H(2)O(2)), 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 H(2)O(2) dependent. It is well known that MPO can use leukocyte-derived H(2)O(2); however, it is unknown whether the vascular-bound MPO can use high-glucose-stimulated, vascular non-leukocyte-derived H(2)O(2) 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 H(2)O(2) 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 H(2)O(2). The results suggest that vascular-bound MPO could use high-glucose-stimulated H(2)O(2) to amplify high-glucose-induced injury in the vascular wall. MPO/H(2)O(2)/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.
authors.affiliation: Vascular Biology Center of Excellence, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave., Coleman Bldg., H300, Memphis, TN 38163, USA. czhang@utmem.edu.
authors.forename: Chunxiang
authors.initials: C
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Jennings
mesh_terms: D000818:Animals; D001011:Aorta; D002339:Carotid Arteries; D003925:Diabetic Angiopathies / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D007962:Leukocytes / Q000201:enzymology / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009195:Peroxidase / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D009195:Peroxidase; D005947:Glucose