Abstract
ObjectivePulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterial hypertension (PAH) show similarities 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 PAH. We therefore explored the involvement of p53 in the monocrotaline (MCT) rat model of pulmonary hypertension (PH) and the pathophysiological consequences of p53 inactivation in response to animal treatment with pifithrin-α (PFT, an inhibitor of p53 activity).Methods and ResultsPH development was assessed by pulmonary arterial pressure, right ventricular hypertrophy and arterial wall thickness. The effect of MCT and PFT on lung p53 pathway expression was evaluated by western blot. Fourteen days of daily PFT treatment (2.2 mg/kg/day), similar to a single injection of MCT (60 mg/kg), induced PH and aggravated MCT-induced PH. In the first week after MCT administration and prior to PH development, p53, p21 and MDM2 protein levels were significantly reduced; whereas PFT administration effectively altered the protein level of p53 targets. Anti-apoptotic and pro-proliferative effects of PFT were revealed by TUNEL and MTT assays on cultured human PA-SMCs treated with 50 μM PFT.ConclusionsPharmacological inactivation of p53 is sufficient to induce PH with a chronic treatment by PFT, an effect related to its anti-apoptotic and pro-proliferative properties. The p53 pathway was down-regulated during the first week in the rat MCT model. These in vivo experiments implicate the p53 pathway at the initiation stages of PH pathogenesis.
Highlights
Pulmonary arterial hypertension (PAH) is a rare and severe disease in which pressure elevation in the pulmonary arteries (PA) leads to right heart failure and death
pulmonary hypertension (PH) development was assessed by pulmonary arterial pressure, right ventricular hypertrophy and arterial wall thickness
Anti-apoptotic and pro-proliferative effects of PFT were revealed by TUNEL and MTT assays on cultured human Pulmonary artery smooth muscle cells (PA-SMCs) treated with 50 μM PFT
Summary
Pulmonary arterial hypertension (PAH) is a rare and severe disease in which pressure elevation in the pulmonary arteries (PA) leads to right heart failure and death. The fundamental cause remains elusive, many disease-predisposing and functionmodifying features of PA-SMCs have been identified. These include inflammation, cross-talk with pulmonary artery endothelial cells (PA-ECs), and BMPRII gene mutations [4,5]. Several studies indicate that PA-SMCs from iPAH patients express abnormal phenotypes ex vivo, when separated from the influence of endothelial and inflammatory cells. These reports suggest intrinsic alterations in PA-SMCs characteristics resulting in dysfunctions in the signaling pathways that control cell cycle progression and proliferation
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