on October 13, 2005
Published online before print October 13, 2005, doi: 10.1161/01.ATV.0000190673.41925.9B
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Submitted on January 12, 2005
Accepted on October 5, 2005
Mechanisms of Increased Vascular Superoxide Production in an Experimental Model of Idiopathic Dilated Cardiomyopathy
Hanke Mollnau ;
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., T.H.); Medizinische Klinik II, Kardiologie, Universitätsklinik Homburg, Homburg (G.N.); and Institut für Physiologie, Universitätsklinikum Frankfurt, Frankfurt (I.F.), Germany.
* To whom correspondence should be addressed. 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.
Key words: oxidative stress • congestive heart failure • vasculature
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