Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is a fatal and progressive disease characterized by pulmonary vascular wall hypertrophy and obliterative vascular lesions. The tumor suppressor, p53, is a transcription factor that regulates the expression of stress response genes, has been extensively investigated under malignant conditions, and its non-canonical functions have recently been implicated in pulmonary vascular disease. The purpose of this study was to examine whether p53 contributes to the development of pulmonary vasoconstriction and vascular remodeling.
Methods: Western blot determined expression levels of p53 in the endothelium-denuded pulmonary artery (PA) or whole lungs isolated from normoxic and hypoxic mice. Ubiquitous MDM2 transgenic mice (MDM2TG), MDM2 mutant transgenic mice (MDM2mut-TG), and wildtype (WT) littermates (6-8 weeks) were exposed to chronic hypoxia (CH, 10% O2) to induce PH. The isolated perfused/ventilated mouse lung was used to determine hypoxic pulmonary vasoconstriction.
Results: Compared to controls, p53 was downregulated in PA (primarily PA smooth muscle cells (PASMC)) after CH exposure (0.43±0.11 vs. 0.17±0.02, n=4), but upregulated in whole lung tissue (primarily PA endothelial cells (PAEC)) (0.41±0.10 and 0.62±0.07, n=4). In MDM2mut-TG mice, the CH-mediated increase in right ventricular systolic pressure (RVSP) (36±3.0 and 27±2.0 mmHg, n=3, p<0.05) and Fulton Index (RV/(LV+S)) (0.43±0.02 and 0.32±0.02, n=3, p<0.05) were significantly attenuated compared to WT mice. MDM2TG mice, however, spontaneously developed mild PH under normoxic conditions. CH significantly increased RVSP (36±3.0, 29±2.1 and 27±2.0 mmHg, n=3, p<0.05) and Fulton Index (14±0.81, 8.8±0.40 and 8±0.80; n=3, p<0.05) in MDM2TG mice compared to both WT and MDM2mut-TG mice.
Conclusions: These results indicate that downregulated p53 in PASMC and upregulated p53 in PAEC both contribute to the development and progression of pulmonary hypertension. MDM2-p53 signaling may be involved in the transcriptional downregulation and upregulation of p53 in PASMC and PAEC, respectively. Targeting the MDM2/p53 signaling pathway may be an important strategy to develop novel therapies for pulmonary hypertension.