TAK-242 suppresses lipopolysaccharide-induced inflammation in human coronary artery endothelial cells.

: TAK-242 (resatorvid), a novel small-molecule cyclohexene derivative, inhibits TLR4 signaling selectively. TAK-242 blocked the Toll-like receptor (TLR) 4-triggered inflammatory signaling by binding directly to a specific amino acid Cys747 in the intracellular domain of TLR4. The present study was designed to examine the effects of TAK-242 on vascular inflammatory responses in human coronary artery endothelial cells (HCAECs) challenged by lipopolysaccharide (LPS, a TLR4 ligand). The results show that TAK-242 attenuated the LPS-induced expression of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein 1 both at the transcription and translation levels in HCAECs. LPS-induced endothelial cell adhesion molecules, intercellular adhesion molecular-1 and vascular cell adhesion molecule-1 expressions were also reduced by treatment with TAK-242. In addition, coincubation with TAK-242 did not effect the expression of TLR4 in LPS-activated HCAECs. Furthermore, TAK-242 efficiently suppressed LPS-induced phosphorylation of nuclear factor κB (NF-κB) and IL-1 associated kinase-1 (IRAK-1) in HCAECs. These findings show that TAK-242 can suppress endothelial cell inflammation, suggesting that TAK-242 might be suitable for development as a therapeutic agent for inflammatory cardiovascular disease.