Inhibition of Monocyte Adhesion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-like Peptide-1 Receptor Agonist, Exendin-4

Abstract

OBJECTIVE Exogenous administration of glucagon-like peptide-1 (GLP-1) or GLP-1 receptor agonists such as an exendin-4 has direct beneficial effects on the cardiovascular system. However, their effects on atherosclerogenesis have not been elucidated. The aim of this study was to investigate the effects of GLP-1 on accumulation of monocytes/macrophages on the vascular wall, one of the earliest steps in atherosclerogenesis. RESEARCH DESIGN AND METHODS After continuous infusion of low (300 pmol · kg−1 · day−1) or high (24 nmol · kg−1 · day−1) dose of exendin-4 in C57BL/6 or apolipoprotein E–deficient mice (apoE−/−), we evaluated monocyte adhesion to the endothelia of thoracic aorta and arteriosclerotic lesions around the aortic valve. The effects of exendin-4 were investigated in mouse macrophages and human monocytes. RESULTS Treatment with exendin-4 significantly inhibited monocytic adhesion in the aortas of C57BL/6 mice without affecting metabolic parameters. In apoE−/− mice, the same treatment reduced monocyte adhesion to the endothelium and suppressed atherosclerogenesis. In vitro treatment of mouse macrophages with exendin-4 suppressed lipopolysaccharide-induced mRNA expression of tumor necrosis factor-α and monocyte chemoattractant protein-1, and suppressed nuclear translocation of p65, a component of nuclear factor-κB. This effect was reversed by either MDL-12330A, a cAMP inhibitor or PKI14-22, a protein kinase A–specific inhibitor. In human monocytes, exendin-4 reduced the expression of CD11b. CONCLUSIONS Our data suggested that GLP-1 receptor agonists reduced monocyte/macrophage accumulation in the arterial wall by inhibiting the inflammatory response in macrophages, and that this effect may contribute to the attenuation of atherosclerotic lesion by exendin-4.