p53 dysfunction increased mitochondrial biogenesis and bronchial smooth muscle cell proliferation in asthma

Introduction: Asthma is a frequent respiratory disease characterized by an airway remodeling. Increase of bronchial smooth muscle (BSM) mass is a crucial feature of such a remodeling since it correlates with the decrease in lung function. The mechanisms of such an increased BSM mass are complex but involve an increased proliferation of asthmatic BSM cells, which involved an enhanced mitochondrial biogenesis. Major tumor suppressor protein p53 is a key cell regulator involved in cell proliferation and has also been implicated in mitochondrial biogenesis. However, the role of p53 in BSM cell proliferation and mitochondrial biogenesis has not been investigated so far. The objective was thus to evaluate the role of p53 in asthmatic BSM cell proliferation and mitochondrial biogenesis. Methods: We assessed the expression of p53 in vitro using flow cytometry and western blot but also ex vivo using laser microdissection and RT-PCR. Using shRNA lentivirus targeting p53, we assessed the role of p53 in both asthmatic and control BSM cells proliferation using both BrdU and cell counting. We analyzed the effect of the down regulation of p53 protein on the regulation of p21, Bax, TFAM and PGC-1a mRNA. Results: P53 expression was increased in asthmatic BSM both ex vivo and in vitro , with a decreased interaction with Mdm2. P53 is unable to inhibit the transcription of TFAM and PGC-1a in asthmatic BSM. As a consequence, p53 cannot slow down the increased mitochondrial biogenesis and the subsequent increased proliferation of asthmatic BSM cells. Conclusions: This work highlights p53 as a new potential therapeutic target against BSM remodeling in asthma.