Differential roles of p38 MAPK and ERK1/2 in angiopoietin-2-mediated rat pulmonary microvascular endothelial cell apoptosis induced by lipopolysaccharide.

Angiopoietin-2 (Ang-2) is a Tie-2 ligand that destabilizes vascular structures, enhances vascular permeability and induces vascular regression and endothelial cell apoptosis. Although there is evidence for the involvement of the Ang/Tie2 axis in acute lung injury (ALI), the underlying mechanisms involved in Ang-2-induced cell apoptosis are not well understood. In this study, whether Ang-2 contributes to microvascular endothelial cell injury and mediates lipopolysaccharide (LPS)-induced endothelial cell apoptosis and its associated signaling pathways was investigated. Exposure of rat pulmonary microvascular endothelial cells (RPMVECs) to LPS, Ang-2 and related inhibitors was performed to measure the expression levels of Ang-2, the activation of mitogen-activated protein kinases (MAPKs), the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, and expression of the apoptosis-related proteins Bax and Bcl-2 using western blotting, reverse transcription-quantitative polymerase chain reaction, flow cytometry and fluorescence microscopy. The expression of Ang-2 in the RPMVECs was increased by LPS independent of time. The phosphorylation of p38 MAPK and ERK1/2 was significantly upregulated and the activation of apoptosis-related proteins Bax and Bcl was mediated by Ang-2. In addition, inhibition of the p38 pathway by SB203580 attenuated the Ang-2-mediated cell apoptosis, but inhibition of the ERK1/2 pathway by PD98059 exerted an anti-apoptotic effect against Ang-2. In conclusion, LPS-induced apoptosis is partly mediated via stimulation of p38 and ERK1/2 signaling pathways, where Ang-2 acts an inflammation-related factor to participate in the course of cell apoptosis in RPMVECs.