GPR40 Agonism Modulates Inflammatory Reactions in Vascular Endothelial Cells

Endothelial dysfunction is strongly linked with inflammatory responses, which can impact cardiovascular disease. Recently, G protein-coupled receptor 40 (GPR40) has been investigated as a modulator of metabolic stress; however, the function of GPR40 in vascular endothelial cells has not been reported. We analyzed whether treatment of GPR40-specific agonists modulated the inflammatory responses in human umbilical vein endothelial cells (HUVECs). Treatment with LY2922470, a GPR40 agonist, significantly reduced lipopolysaccharide (LPS)-mediated nuclear factor-kappa B (NF-KB) phosphorylation and movement into the nucleus from the cytosol. However, treatment with another GPR40 agonist, TAK875, did not inhibit LPS-induced NF-KB activation. LPS treatment induced expression of adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and attachment of THP-1 cells to HUVECs, which were all decreased by LY2922470 but not TAK875. Our results showed that ligand-dependent agonism of GPR40 is a promising therapeutic target for overcoming inflammatory reactions in the endothelium.

Automated summary

Endothelial dysfunction is closely related to inflammatory responses, and G protein-coupled receptor 40 (GPR40) plays an important role in modulating inflammatory reactions in vascular endothelial cells. In this study, a specific agonist of GPR40, LY2922470, was found to inhibit the inflammatory responses induced by lipopolysaccharide (LPS), while another agonist, TAK875, had no effect. LY2922470 also reduced the expression of adhesion molecules and the attachment of cells. These findings suggest that GPR40 could be a potential therapeutic target for treating endothelial inflammation.