Anti-inflammatory and atheroprotective properties of glucagon

Although glucagon has been shown to exert pleiotropic actions in various types of cells and organs through the interaction with its receptor, its pathophysiological role in atherosclerotic cardiovascular disease remains unclear. Here, we examined whether and how glucagon could attenuate the progression of atherosclerotic plaques in apolipoprotein E-deficient mice (ApoE(−/−)), an animal model of atherosclerosis. Glucagon (138 or 413 nmol/kg/day) or vehicle was infused to mice at 16 weeks of age. After 4-week treatment, vascular samples were collected for histological and RT-PCR analyses. Human monocytic THP-1 cells were pre-incubated with or without a glucagon receptor antagonist L-168049, and then treated with or without glucagon for 7 h. Gene and protein expressions were determined by RT-PCR and western blot analyses, respectively. High-dose glucagon infusion significantly decreased aortic plaque area and volume in ApoE(−/−) mice, both of which were inversely correlated with plasma glucagon levels. Glucagon infusion also reduced the ratio of pro-inflammatory interleukin-1β to anti-inflammatory interleukin-10 gene expression in aortae. Glucagon receptor was expressed in THP-1 cells, and 1 nM glucagon decreased the ratio of interleukin-1β to interleukin-10 gene expression, which was significantly prevented by L-168049. Our present findings suggest that glucagon could exert atheroprotection partly via its anti-inflammatory property.