Bile Acid Receptor TGR5 Agonism Induces NO Production and Reduces Monocyte Adhesion in Vascular Endothelial Cells
Objective—TGR5 is a G-protein–coupled receptor for bile acids. So far, little is known about the function of TGR5 in vascular endothelial cells.
Approach and Results—In bovine aortic endothelial cells, treatment with a bile acid having a high affinity to TGR5, taurolithocholic acid (TLCA), significantly increased NO production. This effect was abolished by small interfering RNA–mediated depletion of TGR5. TLCA-induced NO production was also observed in human umbilical vein endothelial cells measured via intracellular cGMP accumulation. TLCA increased endothelial NO synthaseser1177 phosphorylation in human umbilical vein endothelial cells. This response was accompanied by increased Aktser473 phosphorylation and intracellular Ca2+. Inhibition of these signals significantly decreased TLCA-induced NO production. We next examined whether TGR5-mediated NO production affects inflammatory responses of endothelial cells. In human umbilical vein endothelial cells, TLCA significantly reduced tumor necrosis factor-α–induced adhesion of monocytes, vascular cell adhesion molecule-1 expression, and activation of nuclear factor-κB. TLCA also inhibited lipopolysaccharide-induced monocyte adhesion to mesenteric venules in vivo. These inhibitory effects of TLCA were abrogated by NO synthase inhibition.
Conclusions—TGR5 agonism induces NO production via Akt activation and intracellular Ca2+ increase in vascular endothelial cells, and this function inhibits monocyte adhesion in response to inflammatory stimuli.
- Received June 11, 2012.
- Accepted April 9, 2013.
- © 2013 American Heart Association, Inc.