MSCs attenuate hypoxia induced pulmonary hypertension by activating P53 and NF-kB signaling pathway through TNFα secretion

Abstract

Hypoxia could cause vascular smooth muscle hypertrophy, leading to high pulmonary circulation resistance, pulmonary artery (PA) pressure, even pulmonary arterial hypertension (PAH). Recent studies have demonstrated the ability of mesenchymal stem cell (MSC) to ameliorate PAH but the mechanism was controversial. In this study, we revealed that the growth rate of pulmonary artery smooth muscle cells (PASMCs) treated with hypoxia was significantly increased than normal and showed lower expression of potassium channels. However, cells co-cultured with MSC showed decreased proliferation capability and down-regulated expression of ion channel of PAMSCs. The protein array data showed that the changes of PAMSCs was substantially associated with a high level of tumor necrosis factor alpha (TNFα) secretion from MSC. We further demonstrated that TNFα rescued the cell behavior of PAMSCs through activating the expression of P53 and NF-kB and inducing cell cycle arrest by P21/CDK2/CDK4 downregulation. These findings suggested that MSCs could attenuate abnormal function of PAMSCs by TNFα secretion, which was more or less associated with the beneficial effects of MSC on improving PAH.