Imbalance between cell proliferation and apoptosis may underlie the development of PAH (Pulmonary Arterial Hypertension). Survivin is a member of the apoptosis inhibitor gene family involved in cell proliferation. This study aimed to explore if the expression of survivin is increased in a mice model of PAH. We also investigated the effects of the survivin inhibitor (YM155) in the mice model. C57/BL6 mice were exposed to hypoxia and SU5416 (injected s.c. weekly) for 3 weeks. YM155, a suppressor of survivin expression, was also administered s.c. during 7 days the third week after hypoxia and SU5416 injection. We measured right ventricular systolic pressure (RVSP) and right ventricle (RV) hypertrophy by the Fulton index. Vascular remodeling and survivin expression were assessed in lung sections by immunohistochemistry for smooth muscle actin (SMA) and survivin, respectively. Survivin gene and protein expression were evaluated by qPCR and western blot, respectively.
Compared with controls, SU5416+hypoxia treated mice showed a significant increase in RVSP (46±15 vs. 18±5 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/N° vessels+; p=0.002) and an increased expression of survivin in intrapulmonary arteries (23.9% vs. 8.5% survivin+ vessels/ N° vessels+; p=0.0002). Survivin gene and protein expressions were twice higher in SU5416+hypoxia mice compared to controls (p=0.01). Treatment with YM155 reduced RVSP (46±15 in sugen+hypoxia mice vs 24±5 in sugen+hypoxia+YM155 mice; p<0.0001), right ventricular hypertrophy (0.38±0.04 vs 0.32±0.14; p=0.06), vascular remodeling and protein-gene survivin expression (that was twice higher in mice exposed to hypoxia and SU5416 compared with mice exposed to SU5416+hypoxia+YM155 (p=0.003)). Survivin expression is increased in the SU5416+hypoxia experimental mice model of PAH and concomitant treatment with YM155 prevents the development of PAH. These results suggest that survivin is involved in the pathogenesis of PAH and might represent a potential therapeutic target.
Funded by FIS (PI17/1515) and SOCAP