361 - Endothelial-Transcytosed Myeloperoxidase Promotes Endothelial Dysfunction in an Oxidant Specific Manner: Novel Protective Actions of Thiocyanate and Nitrite

Abstract

During cardiovascular disease myeloperoxidase (MPO) released by circulating leukocytes is transcytosed into the sub-endothelial matrix of arteries. At this site, MPO catalyzes oxidative reactions that promote endothelial dysfunction. In the presence of H 2 O 2 , MPO generates several oxidants including conversion of chloride (Cl – ) into hypochlorous acid (HOCl), thiocyanate (SCN – ) into hypothiocyanous acid (HOSCN) or nitrite (NO 2 – ) into nitrogen dioxide radical ( ● NO 2 ), the latter forming 3-nitrotyrosine. Here we studied the implications of these different oxidants produced by endothelial-transcytosed MPO for endothelial function in intact arteries. Incubation of isolated aorta with MPO resulted in its accumulation into the endothelium. Exposure of MPO-containing arteries to H 2 O 2 or angiotensin II elevated aortic levels of HOCl or superoxide (O 2 ●– ) and impaired endothelial-dependent vasorelaxation in a manner restored by removal of Cl – or addition of MPO inhibitors and scavengers of HOCl or O 2 ●– . Addition of SCN – or NO 2 – to MPO-containing aortas also inhibited HOCl and O 2 ●– levels and preserved endothelial-dependent relaxation, despite NO 2 – increasing endothelial 3-nitrotyrosine levels. In an in vivo model of MPO-dependent endothelial dysfunction, LPS administration to wild-type mice induced MPO accumulation into the aortic endothelium, increased O 2 ●– and impaired endothelial-dependent relaxation, events absent or reduced in LPS-treated MPO -/- mice. Ex vivo treatment of aorta from LPS-treated mice with O 2 ●– scavengers improved endothelial function. This study supports that HOCl produced by transcytosed MPO impairs endothelial function by elevating O 2 ●–- . SCN – or NO 2 – protect against MPO-induced endothelial dysfunction by diverting MPO to produce the less damaging oxidants, HOSCN or ● NO 2 . Although 3-nitrotyrosine is considered a deleterious modification our data indicate that its formation correlates with protection in the context of endothelial dysfunction induced by MPO.