title: Chronic hypoxia induces right heart failure in caveolin-1-/- mice.
abstract: Caveolin-1 (Cav-1)-/- mice develop mild pulmonary hypertension as they age. In this study, we sought to determine the effect of chronic hypoxia, an established model of pulmonary hypertension, on young Cav-1-/- mice with no measurable signs of pulmonary hypertension. Exposure of Cav-1-/- mice to chronic hypoxia resulted in an initial rise in right ventricular (RV) systolic pressure (RVSP) similar to wild-type (WT) mice. By three weeks RVSP decreased in the Cav-1-/- mice, whereas it was maintained in WT mice. The drop in RVSP in Cav-1-/- mice was accompanied by decreased cardiac output, increased RV hypertrophy, RV interstitial fibrosis, decreased RV sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a mRNA and decreased RV function compared with WT mice. Importantly, minimal differences were noted in pulmonary vascular remodeling between WT and Cav-1-/- mice, and left ventricular function was normal in hypoxic Cav-1-/- mice. Mechanistically, increased endothelial nitric oxide synthase uncoupling and increased tyrosine nitration of protein kinase G were detected in the RV of Cav-1-/- mice. These hemodynamic, histological, and molecular changes were prevented in Cav-1-/- mice expressing an endothelial-specific Cav-1 transgene or by nitric oxide synthase inhibition. These data suggest that, in Cav-1-/- mice, increased oxidative/nitrosative stress due to endothelial nitric oxide synthase uncoupling modifies the response of the RV to pressure overload, accelerating the deterioration of RV function.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: J Agustin
authors.initials: JA
authors.lastname: Cruz
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Bauer
authors.forename: Andres I
authors.initials: AI
authors.lastname: Rodriguez
authors.forename: Archana
authors.initials: A
authors.lastname: Gangopadhyay
authors.forename: Nabil S
authors.initials: NS
authors.lastname: Zeineh
authors.forename: Yinna
authors.initials: Y
authors.lastname: Wang
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: Philip M
authors.initials: PM
authors.lastname: Bauer
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002302:Cardiac Output / Q000502:physiology; D051242:Caveolin 1 / Q000235:genetics*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology
chemical_list: D051242:Caveolin 1; D052250:Nitric Oxide Synthase Type III; D017869:Cyclic GMP-Dependent Protein Kinases