Chronic NOS inhibition prevents adverse lung remodeling and pulmonary arterial hypertension in caveolin-1 knockout mice.
Recently generated caveolin-1 deficient mice (cav-1 ko) suffer from severe lung fibrosis with marked pulmonary hypertension and arterial hypoxemia and may therefore serve as an useful animal model of this devastating human disorder. Accumulating evidence strongly supports the negative regulatory influence of caveolin-1 on endothelial nitric oxide synthase resulting in a constitutive hyperactivation of the nitric oxide (NO) pathway in cav-1 ko. We therefore hypothesized that a disturbed NO signaling is implicated in the evolution of the adverse lung phenotype of cav-1 ko. For this purpose, cav-1 ko of 2 months age were compared with knockout counterparts experiencing 2-month postnatal NO synthase inhibition by NG-nitro-l-arginine methyl ester (L-NAME) treatment. Chronic l-NAME administration prevented adverse lung remodeling in cav-1 ko. Furthermore, l-NAME donation led to a normalized oxygen saturation (91.5+/-1.8% vs. 98.5+/-2.3%, P<0.01, n=10-12), a marked decrease in right ventricular hypertrophy (LV/RV ratio: 4.0+/-0.3 vs. 2.7+/-0.3, P<0.01, n=10-12) and reductions of the elevated pulmonary artery pressure (40.2+/-3.1 mmHg vs. 26.3+/-4.6 mmHg, P<0.01, n=6). Collectively, these improvements resulted in an enhanced exercise capacity of l-NAME-treated cav-1 ko. Finally, we found evidence for enhanced oxidative stress in untreated cav-1 ko which was substantially reduced by chronic l-NAME administration to cav-1 ko. In view of these data, we speculate that a perturbation of NO signaling, together with enhanced O2(-) production originating from NO synthases, may play a pivotal role in the pathogenesis of the adverse pulmonary phenotype seen in cav-1 ko.
Wunderlich
Carsten
C
Department of Cardiology, Medical Clinic, University of Technology Dresden, Fetscherstr. 76, Dresden 01307, Germany. carstenwunderlich@gmx.de <carstenwunderlich@gmx.de>
Schmeisser
Alexander
A
Heerwagen
Christian
C
Ebner
Bernd
B
Schober
Kristin
K
Braun-Dullaeus
Ruediger C
RC
Schwencke
Carsten
C
Kasper
Michael
M
Morawietz
Henning
H
Strasser
Ruth H
RH
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D051242:Caveolin 1 / Q000235:genetics* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000503:physiopathology / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009929:Organ Size / Q000187:drug effects; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010641:Phenotype; D010805:Physical Conditioning, Animal / Q000502:physiology; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology*; D012129:Respiratory Function Tests; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
D051242:Caveolin 1; D004791:Enzyme Inhibitors; D016877:Oxidants; D013481:Superoxides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester