Enhanced Tyrosine Nitration of Prostacyclin Synthase Is Associated with Increased Inflammation in Atherosclerotic Carotid Arteries from Type 2 Diabetic Patients

Prostacyclin synthase (PGIS) is tyrosine nitrated in diseased animals. Whether PGIS nitration occurs in human diabetic atherosclerotic arteries has not been reported. The present study was designed to determine PG'S nitration and its association with the inflammatory response in atherosclerotic carotid arteries from patients with or without type 2 diabetes, and carotid plaques were obtained from patients who underwent carotid endarterectomy. PGIS nitration, nitric oxide synthases, adhesion molecules, myeloperoxidase, osteopontin, and matrix metalloproteinase (MMP) were measured by using immunohistochemistry and Western blotting. In low stenosis areas, diabetes enhanced reactive nitrogen species production, as evidenced by increases in 3-nitrotyrosine and PGIS nitration. In parallel, diabetes dramatically increased inflammatory markers including intracellular adhesion molecule-1, vascular adhesion molecule-1, and osteopontin. In both diabetic and nondiabetic patients, MMP-2 and MMP-9 protein levels were significantly increased in the arteries with high stenosis as compared with those with low stenosis. Moreover, diabetes enhanced inducible nitric oxide synthase expression in the plaques from low stenosis areas and up-regulated myeloperoxidase expression in the plaques from both high and low stenosis areas. These data demonstrate that diabetes preferentially increases PGIS nitration that is associated with excessive vascular inflammation in atherosclerotic carotid arteries from patients with type 2 diabetes, suggesting a possible role of tyrosine nitration of PGIS in the development of atherosclerosis in patients with diabetes. (Am J Pathol 2010, 176:2542-2549; DOI: 10.2353/ajpath.2010.090783)