Abstract

Cruz JA, Bauer EM, Rodriguez AI, Gangopadhyay A, Zeineh NS, Wang Y, Shiva S, Champion HC, Bauer PM. Chronic hypoxia induces right heart failure in caveolin-1 -/- mice. Am J Physiol Heart Circ Physiol 302: H2518-H2527, 2012. First published April 13, 2012; doi:10.1152/ajpheart.01140.2011.-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 Ca2+-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.