Mechanisms of increased vascular superoxide production in an experimental model of idiopathic dilated cardiomyopathy.
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.
Mollnau
Hanke
H
Medizinische Klinik II, Johannes Gutenberg Universität, Mainz, Germany.
Oelze
Matthias
M
August
Michael
M
Wendt
Maria
M
Daiber
Andreas
A
Schulz
Eberhard
E
Baldus
Stephan
S
Kleschyov
Andrei L
AL
Materne
Anke
A
Wenzel
Philip
P
Hink
Ulrich
U
Nickenig
Georg
G
Fleming
Ingrid
I
Münzel
Thomas
T
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
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