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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2554.)
© 2005 American Heart Association, Inc.

Vascular Biology

Mechanisms of Increased Vascular Superoxide Production in an Experimental Model of Idiopathic Dilated Cardiomyopathy

Hanke Mollnau; Matthias Oelze; Michael August; Maria Wendt; Andreas Daiber; Eberhard Schulz; Stephan Baldus; Andrei L. Kleschyov; Anke Materne; Philip Wenzel; Ulrich Hink; Georg Nickenig; Ingrid Fleming; Thomas Münzel

From the Medizinische Klinik II, Johannes Gutenberg Universität, Mainz (H.M., M.O., A.D., A.L.K., U.H., T.M.); Medizinische Klinik III, Kardiologie und Angiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg (M.A., M.W., S.B., A.M.); Medizinische Klinik II, Kardiologie, Universitätsklinik Homburg, Homburg (G.N.); and Institut für Physiologie, Universitätsklinikum Frankfurt, Frankfurt (I.F.), Germany.

Correspondence to Thomas Münzel MD, Medizinische Klinik II, Johannes Gutenberg Universität Mainz, Langenbeckstrasse 1, 55101 Mainz/Germany. E-mail tmuenzel{at}uni-mainz.de

Objective— In the present study, we sought to identify mechanisms underlying increased oxidative stress in vascular tissue in an experimental animal model of chronic congestive heart failure (CHF).

Methods and Results— Superoxide and nitric oxide (NO) was measured in vessels from cardiomyopathic hamsters (CHF hamsters) and golden Syrian hamsters. We also determined expression of endothelial nitric oxide synthase (NOSIII), the soluble guanylyl cyclase, the cGMP-dependent kinase, and the NADPH oxidase. To analyze the contribution of the renin-angiotensin system to oxidative stress, CHF hamsters were treated with the angiotensin-converting enzyme inhibitor captopril for 200 days (120 mg · kg^–1 · d^–1). CHF led to increased superoxide production by NOSIII and the NADPH oxidase. Decreased NO production in CHF was associated with a decrease in the expression of NOSIII and an inhibition of NO downstream signaling in the aorta. NOSIII expression was increased within the left ventricle. Captopril treatment normalized NOSIII expression in vessels and the myocardium, reduced superoxide levels, and prevented NOSIII uncoupling. Accordingly, endothelial function, NO production, and downstream signaling were improved in CHF vessels.

Conclusions— Oxidative stress in CHF is mediated by NADPH oxidase and an uncoupled NOSIII secondary to an activation of the renin-angiotensin system leading to impaired NO downstream signaling.

In vessels from cardiomyopathic hamsters, we identified NOSIII and NADPH oxidase as significant superoxide sources. Oxidative stress was associated with a decrease in vascular NO production and NOSIII expression, leading to inhibition of NO downstream signaling. Captopril treatment prevented these phenomena, indicating a crucial role of the renin-angiotensin-aldosterone system.

Key Words: oxidative stress • congestive heart failure • vasculature • captopril • NOSIII uncoupling

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