RT Journal Article
SR Electronic
T1 Caspase inhibition stabilizes progressive vascular remodeling in established pulmonary hypertension
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP PA4912
DO 10.1183/13993003.congress-2015.PA4912
VO 46
IS suppl 59
A1 C.M. Happé
A1 R. Szulcek
A1 N. Rol
A1 M.A. De Raaf
A1 I. Schalij
A1 A. Vonk-Noordegraaf
A1 F.S. De Man
A1 G.P. Van Nieuw-Amerongen
A1 H.J. Bogaard
YR 2015
UL http://erj.ersjournals.com/content/46/suppl_59/PA4912.abstract
AB Pulmonary arterial hypertension (PAH) is characterized by exuberant cell growth and vascular remodeling that is believed to be caused by a phenotypic switch of the endothelium towards apoptosis resistance and hyper-proliferation. On the contrary, recent animal models provided evidence that apoptosis rates continue to be high resulting in an increased cell turnover. Therefore we tested, whether ongoing apoptosis is required to maintain high rates of proliferation and vascular remodeling in established PH.Sugen-hypoxia (SuHx) rats with established progressive PH were treated for 2 weeks with the pan-caspase inhibitor Z-Asp (2mg 3x/pw) to inhibit apoptosis. Pulmonary vascular resistance decreased (mmHg/ml.min, 0.83±0.24 vs. 0.45±0.14, p=0.003), along with a decreased intima fraction thickness (28%±4.4% vs. 16%±2.5%, p=0.01) and reduced fraction of occlusions (p=0.0464). Histology revealed a significant decrease in both apoptotic and proliferative activities, as measured by a decrease in cleaved caspase 3 (no. of +-cells, 0.6±0.1 vs. 0.2±0.1, p=0.02) – and proliferating cell nuclear antigen (no. of +-cells, 1.5±.4 vs. 0.8±0.2, p=0.05) lung vascular endothelial cells.In conclusion, we show that caspase inhibition attenuates progressive vascular remodeling in established experimental pulmonary hypertension. This data suggest that new PAH treatment concepts should consider prevention of apoptosis rather than induction.