Progressive endothelial cell damage in an inflammatory model of pulmonary hypertension

ABSTRACTMonocrotaline (MCT)-induces progressive disruption of endothelial cell membrane and caveolin-1 leading to pulmonary arterial hypertension (PAH). Treatment instituted early rescues caveolin-1 and attenuates PAH. To test the hypothesis that the poor response to therapy in established PAH is due to progressive deregulation of multiple signaling pathways, the authors investigated time-dependent changes in the expression of caveolin-1, gp130, PY-STAT3, Bcl-xL, and the molecules involved in NO signaling pathway (endothelial nitric oxide synthase [[eNOS]], heat sock protein 90 [[HSP90]], Akt, soluble guanylate cyclase [[sGC]] α1 and β1 subunits). PAH and right ventricular hypertrophy (RVH) were observed at 2 and 3 weeks. Progressive loss of endothelial caveolin-1 and sGC (α1, β1), PY-STAT3 activation, and Bcl-xL expression were observed at 1 to 3 weeks post-MCT. The expression of gp130 increased at 48 hours and 1 week, with a subsequent loss at 2 and 3 weeks. The expression of eNOS increased at 48 hours ...