title: Mechanisms of increased vascular superoxide production in an experimental model of idiopathic dilated cardiomyopathy.
abstract: 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).
  
  
  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.
authors.affiliation: Medizinische Klinik II, Johannes Gutenberg Universität, Mainz, Germany.
authors.forename: Hanke
authors.initials: H
authors.lastname: Mollnau
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Michael
authors.initials: M
authors.lastname: August
authors.forename: Maria
authors.initials: M
authors.lastname: Wendt
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Kleschyov
authors.forename: Anke
authors.initials: A
authors.lastname: Materne
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hink
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001835:Body Weight; D002216:Captopril / Q000494:pharmacology; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D006162:Guanylate Cyclase; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D008840:Microfilament Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009929:Organ Size; D018384:Oxidative Stress / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D013481:Superoxides / Q000378:metabolism*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; C079789:neutrophil cytosol factor 67K; D000098662:Vasodilator-Stimulated Phosphoprotein; D013481:Superoxides; D009569:Nitric Oxide; D002216:Captopril; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase