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Interaction of myeloperoxidase with vascular NAD(P)H oxidase-derived reactive oxygen species in vasculature: implications for vascular diseases

Vascular Biology Center of Excellence, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Submitted 8 August 2003 ; accepted in final form 11 August 2003

Vascular NAD(P)H oxidase-derived reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂) have emerged as important molecules in the pathogenesis of atherosclerosis, hypertension, and diabetic vascular complications. Additionally, myeloperoxidase (MPO), a transcytosable heme protein that is derived from leukocytes, is also believed to play important roles in the above-mentioned inflammatory vascular diseases. Previous studies have shown that MPO-induced vascular injury responses are H₂O₂ dependent. It is well known that MPO can use leukocyte-derived H₂O₂; however, it is unknown whether the vascular-bound MPO can use vascular nonleukocyte oxidase-derived H₂O₂ to induce vascular injury. In the present study, ANG II was used to stimulate vascular NAD(P)H oxidases and increase their H₂O₂ production in the vascular wall, and vascular dysfunction was used as the vascular injury parameter. We demonstrated that vascular-bound MPO has sustained activity in the vasculature. MPO could use the vascular NAD(P)H oxidase-derived H₂O₂ to produce hypochlorus acid (HOCl) and its chlorinating species. More importantly, MPO derived HOCl and chlorinating species amplified the H₂O₂-induced vascular injury by additional impairment of endothelium-dependent relaxation. HOCl-modified low-density lipoprotein protein (LDL), a specific biomarker for the MPO-HOCl-chlorinating species pathway, was expressed in LDL and MPO-bound vessels with vascular NAD(P)H oxidase-derived H₂O₂. MPO-vascular NAD(P)H oxidase-HOCl-chlorinating species may represent a common pathogenic pathway in vascular diseases and a new mechanism involved in exacerbation of vascular diseases under inflammatory conditions.

endothelial dysfunction; atherosclerosis; inflammation; leukocyte

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