Abstract 19887: Inactivation of P53 is Sufficient to Induce Development of Pulmonary Hypertension
Objectives: Growing evidence suggest that pulmonary hypertension (PH) and cancer share physiopathological characteristics. In particular, pulmonary artery smooth muscle cells (PA-SMCs) showed hyper-proliferation, apoptosis resistance, metabolic disorders, genomic instability and excessive inflammation similar to cancer cells. Due to the growth-suppressive and pro-apoptotic effects of p53, and its inactivation in cancer, we hypothesized that the p53 pathway could be altered in PH. We therefore explored the consequence of pharmalogical p53 inactivation with pifithrin-α (PFT, an inhibitor of p53 activity) on the development of experimental PH.
Methods: Adult rats were divided into four groups: two groups received a mono-injection of monocrotaline (MCT: 60 mg/kg) and treated daily with PFT (2.2 mg/kg/day) or vehicle and two groups without MCT and treated with PFT or vehicle for 14 days. At the end of the treatment period, PH development was assessed by pulmonary artery pressure (PAP), right ventricular hypertrophy and arterial wall thickness. The effect of MCT and PFT on lung p53 expression was evaluated by western blot. The direct effect of PFT on cell apoptosis and proliferation was assessed in cultured human PA-SMCs and determined by TUNEL and MTT assays respectively.
Results: In the first week after MCT administration and prior to PH development, p53, MDM2 and p21 protein expressions were significantly reduced. PFT administration did not affect p53 protein level, but altered its transcriptional activity as determined by a reduction in p21 and BAX protein levels. Similarly to MCT, PFT treatment induced an increase of PAP, right ventricular hypertrophy and pulmonary vascular remodeling. Furthermore PFT aggravated MCT-induced right ventricular hypertrophy and pulmonary vascular remodeling. On the cellular level, PFT increased the PA-SMCs growth and decreased the number of TUNEL positive cells.
Conclusions: These results implicate the p53 pathway in the initiation stage of PH development in the rat MCT model, due to altered protein level, activity and regulation of p53. PFT-mediated inactivation of p53 is sufficient to induce PH in rats, likely related to its pro-proliferative and anti-apoptotic cellular effects.
Author Disclosures: S. Jacquin: None. V. Rincheval: None. B. Mignotte: None. S. Richard: None. M. Humbert: None. O. Mercier: None. E. Fadel: None. S. Eddahibi: None.
- © 2014 by American Heart Association, Inc.