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.

Regulation of Hypoxia-induced Pulmonary Hypertension by Vascular Smooth Muscle Hypoxia-Inducible Factor-1α

“…Other studies also suggest that pulmonary artery pressure is not the sole factor regulating cardiac hypertrophy, and that cardiac hypoxia itself may be a stimulus for RV remodeling (45,46) through the up-regulation of gene expression (47,48). Animal models of RV pressure overload induced by pulmonary artery banding are not associated with RV failure (49), whereas pressure overload induced by hypoxia is (50,51). Bogaard and coworkers (46) compared the RV hypertrophic response to VEGF receptor inhibition (using SU5416) with that evoked by pulmonary artery banding in chronically hypoxic rats.…”

Bone marrow transplantation prevents right ventricle disease in the caveolin-1–deficient mouse model of pulmonary hypertension

“…26,27 The development of PH in CAV-1 KO mice is accelerated by exposing animals to hypoxia. 28 We and others have reported a myeloid/BM origin of PH. Engraftment of serotonin 2B receptor-deficient BM in wild-type (WT) mice protected against the development of hypoxia-induced pulmonary vascular remodeling and elevation of RVSP in mice.…”

“…Trichrome staining was used to visualize and measure RV fibrosis 28,32,33 A Leica SCN400 F slide scanner (Leica Microsystems, Wetzlar, Germany) was used to scan images of whole slides at 320 magnification. Image Pro Plus 7.0. software was use for quantification of fibrosis area/total tissue area.…”

Nitration of Tyrosine 247 Inhibits Protein Kinase G-1α Activity by Attenuating Cyclic Guanosine Monophosphate Binding

“…Our recent studies have identified nitration and the ensuing attenuation of PKG-1␣ activity in the lungs of lambs with pulmonary hypertension secondary to increased pulmonary blood flow and in lambs with rebound pulmonary hypertension associated with the acute withdrawal of inhaled NO therapy (1). In addition, the nitration and subsequent attenuation of PKG activity in the right ventricle appears to be responsible for the deterioration of right ventricle function in a mouse model of pulmonary hypertensive induced by chronic hypoxia (43). However, the increase in protein nitration associated with hypoxia reduces PKG activity through changes at the transcriptional and post-translational levels (2).…”