GPR40 agonist, an emerging antidiabetic agent, regulates foam cell formation and endothelial cytotoxicity

초록

Background and aims: G protein-coupled receptor 40 (GPR40), a receptor for some fatty acids, is attracting attention as a drug target for anti-hyperglycemia because it can induce glucose-stimulated insulin secretion (GSIS) by regulating intracellular calcium level in the pancreas. Recently, GPR40-mediated anti-oxidative and anti-inflammatory responses have been observed in various cell types. Thus, GPR40 is considered as a key molecule to overcome several metabolic disorders. However, endothelial GPR40 functions remain unclear. Thus, the objective of this study was to determine whether GPR40-specific agonists might protect vascular endothelial cells against metabolic stimuli. Materials and methods: Human umbilical vein endothelial cells (HUVECs) and THP-1 cells were used to investigate effects of GPR40 agonists on endothelium. Results: In phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells, LY2922470, a GPR40 agonist, reduced LPS-mediated low-density lipoprotein receptor (LDLR), CD36 and inducible nitric oxide synthase (iNOS) expression, leading to blockage of LPS-induced LDL uptake. However, these beneficial effects were not detected after treatment with TAK875, another GPR40 agonist, suggesting that GPR40 could regulate the process of foam cell formation in a ligand-dependent manner. We also treated vascular endothelial cells with palmitate to induce cytotoxicity. Both LY2922470 and TAK875 significantly reduced palmitate mediated endoplasmic reticulum (ER) stress, caspase-3 and poly ADP-ribose polymerase (PARP) cleavage and lactate dehydrogenase (LDH) release. These effects were inhibited after treatment with compound C, an inhibitor for adenosine monophosphate-activated protein kinase (AMPK). Conclusion: GPR40 has beneficial effects on metabolic stimuli in vascular endothelial cells and THP-1 cells. Since chronic and excessive inflammation and cytotoxicity are known to be responsible for foam cell formation, plaque development and plaque instability, GPR40 might represent a good therapeutic target to overcome cardiovascular diseases (CVD) such as atherosclerosis.