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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:943.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Angiotensin II Induces Endothelial Xanthine Oxidase Activation

Role for Endothelial Dysfunction in Patients With Coronary Disease

Ulf Landmesser; Stephan Spiekermann; Christoph Preuss; Sajoscha Sorrentino; Dieter Fischer; Costantina Manes; Maja Mueller; Helmut Drexler

From the Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.

Correspondence to Ulf Landmesser, MD, Medizinische Hochschule Hannover, Abteilung Kardiologie und Angiologie, Carl Neuberg Str.130625 Hannover, Germany. E-mail Landmesser.Ulf{at}MH-Hannover.DE

Objective— Xanthine oxidase (XO), a major source of superoxide, has been implicated in endothelial dysfunction in atherosclerosis. Mechanisms, however, leading to endothelial XO activation remain poorly defined. We tested the effect of angiotensin II (Ang II) on endothelial XO and its relevance for endothelial dysfunction in patients with coronary disease.

Methods and Results— XO protein levels and XO-dependent superoxide production were determined in cultured endothelial cells in response to Ang II. In patients with coronary disease, endothelium-bound XO activity as determined by ESR spectroscopy and endothelium-dependent vasodilation were analyzed before and after 4 weeks of treatment with the AT₁-receptor blocker losartan, the XO inhibitor allopurinol, or placebo. Ang II substantially increased endothelial XO protein levels and XO-dependent superoxide production in cultured endothelial cells, which was prevented by NAD(P)H-oxidase inhibition. In vivo, endothelium-bound XO activity was reduced by losartan and allopurinol, but not placebo therapy in patients with coronary disease. XO inhibition with oxypurinol improved endothelium-dependent vasodilation before, but not after losartan or allopurinol therapy.

Conclusions— These findings suggest a novel mechanism whereby Ang II promotes endothelial oxidant stress, ie, by redox-sensitive XO activation. In patients with coronary disease, losartan therapy reduces endothelium-bound XO activity likely contributing to improved endothelial function.

The present study suggests that Ang II increases endothelial cell xanthine oxidase (XO) protein levels and XO-dependent superoxide production. Importantly, endothelium-bound XO activity was markedly reduced in patients with coronary disease after AT₁-receptor blocker treatment by losartan, likely representing a novel mechanism contributing to improved endothelial function after AT₁-receptor blockade.

Key Words: endothelium • coronary disease • free radicals • xanthine oxidase • angiotensin II

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