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

Abstract

OBJECTIVEExogenous 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 METHODSAfter 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.RESULTSTreatment 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.CONCLUSIONSOur 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.

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

“…Two previous reports have implied that GLP-1 analogues might exert anti-inflammatory properties [16,17]. One of them showed that exendin-4 inhibited interleukin-1β-induced inducible nitric oxide synthase at the protein level in RINm5F beta-cells [16].…”

“…One of them showed that exendin-4 inhibited interleukin-1β-induced inducible nitric oxide synthase at the protein level in RINm5F beta-cells [16]. The other report demonstrated that exendin-4 inhibits monocyte adhesion to endothelial cells and attenuates atherosclerotic lesions in apolipoprotein E-deficient mice, in which exendin-4 suppressed NF-κB activation in macrophages [17]. In both reports, the antiinflammatory effect was reversed by cAMP inhibitor or a protein kinase A inhibitor, suggesting that this effect of GLP-1 analogues is mediated through the GLP-1 receptor.…”

Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial

“…31,32 Further cardioprotective effects, by means of increased coronary flow, 29 reduced myocardial infarct size, 33 and improved left ventricular function, have also been suggested by animal data. 30,34 Human mechanistic studies are consistent with these findings demonstrating an improvement in flow-mediated vasodilation in the postprandial state, 13 reduced infarct size in patients with ST-segment elevation myocardial infarction, 12,14 and an improvement in left ventricular ejection fraction in patients with heart failure. 35 These data together justify the conduct of a large-scale, adequately powered outcome trial testing for the superiority of a diabetes treatment regimen containing once-weekly exenatide on cardiovascular outcomes.…”

“…[7][8][9][10][11] In addition, further pleiotropic effects on the cardiovascular system, both through GLP-1 receptor-mediated and other mechanisms, have been suggested. 29 Studies in animal models suggest beneficial effects of GLP-1 on atherogenesis, by inhibiting the inflammatory response in macrophages and endothelial adhesion 30 and modulating endothelial function. 31,32 Further cardioprotective effects, by means of increased coronary flow, 29 reduced myocardial infarct size, 33 and improved left ventricular function, have also been suggested by animal data.…”

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

“…Besides its insulinotropic action, exendin-4 may also exert direct beneficial effects on endothelial function. Exendin-4 reduces macrophage adhesion to the endothelium, an early step in the formation of atherosclerotic plaques and endothelial dysfunction (Arakawa et al 2010). Acute administration of exendin-4 in humans prevents endothelial dysfunction induced by ischemia reperfusion injury (Ha et al 2011) and after a high-fat meal load (Koska et al 2010), effects suggested to be GLP1 receptor and NO dependent (Nyström et al 2004).…”