Activating Mas receptor protects human pulmonary microvascular endothelial cells against LPS‐induced apoptosis via the NF‐kB p65/P53 feedback pathways

Abstract The balance between Ang II/AT1R and Ang‐(1‐7)/Mas plays a pivotal role in the development of lipopolysaccharides (LPS)‐induced acute respiratory distress syndrome. However, the mechanisms underlying the balancing process still remain unclear. Here we investigated the roles of nuclear factor (NF)‐κB and p53 in regulating AT1R and Mas expression. The results demonstrated that Ang II pretreatment resulted in downregulation of Mas and upregulation of AT1R, phosphorylated p65, and apoptosis in LPS‐treated Human pulmonary microvascular endothelial cells (HPMVECs), but had no effect on p53 expression. Lentiviral vector‐mediated P65 knockdown, but not a P53 knockdown, reversed all these effects of Ang II. On the other hand, Ang‐(1‐7) pretreatment lead to an increased in Mas expression and a decrease in AT1R, p53, and phosphorylated p65 expressions with suppressed apoptosis in LPS‐treated cells. P65 knockdown promoted the protein expression of both AT1R and Mas while inhibiting p53 expression. P53 knockdown, but not a p65 knockdown, reversed all these effects of Ang‐(1‐7). Interestingly, p65 overexpression upregulated p53 and AT1R but downregulated Mas. P53 knockdown activated p65. These results suggest that there is a two‐way feedback regulation between AT1R and Mas receptor via the NF‐kB p65/P53 pathway, which may play a key role in LPS‐induced HPMVECs apoptosis.