Abstract
Recently we have shown the glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutide (Lir), inhibits early atherosclerosis development in vivo by modulating immune cell function. We hypothesized Lir could attenuate pre-established disease by modulating monocyte/macrophage phenotype to induce athero-protective responses. Human atherosclerotic plaques obtained post-endarterectomy and human peripheral blood macrophages were treated ex vivo with Lir. In parallel, apolipoprotein E deficient (ApoE-/-) mice received a high-fat, high-cholesterol diet to induce atherosclerosis for 8 weeks, after which ApoE-/- mice received 300μg/kg Lir daily or vehicle control, for a further 4 weeks to investigate attenuation of atherosclerosis. Lir inhibited pro-inflammatory monocyte chemoattractant protein-1 (MCP-1) secretion from human endarterectomy samples and, MCP-1, tumour necrosis factor-alpha (TNF-α) and interleukin-1beta secretion from human macrophages following ex vivo treatment. An increase in CD206 mRNA and IL-10 secretion was also detected which imply resolution of inflammation. Importantly, Lir significantly attenuated pre-established atherosclerosis in ApoE-/- mice in the whole aorta and aortic root. Proteomic analysis of ApoE-/- bone marrow cells showed Lir up-regulated the pro-inflammatory cathepsin protein family, which was abolished in differentiated macrophages. In addition, flow cytometry analysis of bone marrow cells induced a shift towards reduced pro-inflammatory and increased anti-inflammatory macrophages. Lir attenuates pre-established atherosclerosis in vivo via altering pro-inflammatory mediators. This is the first study to describe a mechanism through which Lir attenuates atherosclerosis by increasing bone marrow pro-inflammatory protein expression, which is lost in differentiated bone marrow-derived macrophages. This contributes to our understanding of the anti-inflammatory and cardio-protective role of GLP-1RAs.
SIGNIFICANCE STATEMENT It is critical to understand the mechanisms through which liraglutide (Lir) mediates a cardioprotective effect as many type 2 diabetic medications increase the risk of myocardial infarction and stroke. We have identified that Lir reduces pro-inflammatory immune cell populations and mediators from plaque-burdened murine aortas in vivo and augments proresolving bone marrow-derived macrophages in attenuation of atherosclerotic disease, which provides further insight into the athero-protective effect of Lir.
- The American Society for Pharmacology and Experimental Therapeutics