Abstract
Imbalance between cell proliferation and apoptosis may underlie the development of PAH. PAH is considered as an uncontrolled proliferative process in pulmonary arteries. Survivin is a member of the apoptosis inhibitor gene family involved in cell proliferation. We investigate the potential role of survivin in the pathogenesis of PAH and the effects of the survivin inhibitor (YM155) in a mice model. Mice were exposed to hypoxia+SU5416. YM155, a suppressor of survivin expression, was also administered s.c. after hypoxia+SU5416 injection. Compared with controls, SU5416+hypoxia treated mice showed a significant increase in right ventricular systolic pressure (RVSP) (36±10 vs. 22±3 mmHg; p<0.0001), RV hypertrophy (RV/LV+septum ratio, 0.37±0.07 vs. 0.29±0.02; p=0.0005), vascular remodeling (64.1% vs. 43.6% SMA+ vessels/mm2; p=0.0002) and an increased expression of survivin in intrapulmonary arteries (23.9% vs. 8.5% survivin+ vessels/mm2;p=0.0002). Survivin gene and protein expressions were 5 fold higher in SU5416+hypoxia mice compared to controls (p<0.001). Treatment with YM155 reduced RVSP (46±15 in the SU5416+hypoxia group vs 22±4 in the SU5416+hypoxia+YM155 group; p<0.05), RV hypertrophy (0.38±0.04 vs 0.32±0.14; p=0.06), vascular remodeling and protein-gene survivin expression (that was 4 fold higher in mice exposed to hypoxia and SU5416 compared with mice exposed to SU5416+hypoxia+YM155 (p<0.001)). Survivin expression is increased in the experimental model of PAH. Concomitant treatment with YM155 prevents the development of PAH in this experimental model suggesting that survivin is involved in the pathogenesis of PAH and might represent a potential therapeutic target.
Funded by FIS (PI17/1515) and SOCAP.
Footnotes
Cite this article as: European Respiratory Journal 2019; 54: Suppl. 63, PA5055.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available atwww.ers-education.org(ERS member access only).
- Copyright ©the authors 2019