Abstract 13156: Survivin Inhibition Reverses Cardiac and Pulmonary Remodeling in Monocrotaline-Induced Pulmonary Arterial Hypertension
Introduction: Cardiac and pulmonary expression of the inhibitor of apoptosis survivin and its endogenous inhibitor smac was characterized throughout the progression of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Therapeutic effects of the survivin antagonist terameprocol (TMP) were assessed, both in vitro and in vivo.
Methods: Protocol I: adult male Wistar rats received a subcutaneous injection of MCT (60 mg/Kg) or equal volume of vehicle. On days 1, 3, 7, 14 and 21 after injection (n=7-12 per group per time-point), right ventricular (RV) pressures were measured, heart and lungs were weighted and collected for histological analysis, immunohistochemistry and western blot. Protocol II: adult male Wistar rats injected with MCT were treated with TMP (166 mg/Kg, ip; MCT-TMP, n=7) or vehicle (MCT-V, n=9) on days 7, 12 and 17 after injection and compared with a SHAM group (n=7). On day 21, cardiac output and RV pressures were measured and heart and lungs were weighted and collected for histological analysis. Protocol III: Primary cultures of pulmonary artery smooth muscle cells (PASMC) were established from sham and MCT-treated rats (day 21) in order to assess the effects of TMP in proliferation and apoptosis.
Results: Survivin upregulation and smac downregulation were present since day 7 after MCT injection and preceded the hemodynamic manifestations of PAH. Increases in RV peak systolic pressure, dP/dtmax and dP/dtmin were only present since day 14. In vivo, TMP treatment reduced RV hypertrophy and pulmonary arterial wall thickness, decreased RV peak systolic pressure, dP/dtmax and dP/dtmin and normalized cardiac output. TMP inhibited proliferation and induced apoptosis of PASMC in a dose-dependent manner.
Conclusions: Our findings suggest that survivin has an important role in PAH. TMP could be an effective and highly selective therapeutic strategy for PAH by reversing cardiac and pulmonary remodeling and improving hemodynamic features.
- © 2013 by American Heart Association, Inc.