Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used to treat diabetes and obesity and reduce rates of major cardiovascular events, such as stroke and myocardial infarction. Nevertheless, the identity of GLP-1R–expressing cell types mediating the cardiovascular benefits of GLP-1RA remains incompletely characterized. Herein, we investigated the importance of murine Glp1r expression within endothelial and hematopoietic cells. Mice with targeted inactivation of Glp1r in Tie2+ cells exhibited reduced levels of Glp1r mRNA transcripts in aorta, liver, spleen, blood, and gut. Glp1r expression in bone marrow cells was very low and not further reduced in Glp1rTie2–/– mice. The GLP-1RA semaglutide reduced the development of atherosclerosis induced by viral PCSK9 expression in both Glp1rTie2+/+ and Glp1rTie2–/– mice. Hepatic Glp1r mRNA transcripts were reduced in Glp1rTie2–/– mice, and liver Glp1r expression was localized to γδ T cells. Moreover, semaglutide reduced hepatic Tnf, Abcg1, Tgfb1, Cd3g, Ccl2, and Il2 expression; triglyceride content; and collagen accumulation in high-fat, high-cholesterol diet–fed Glp1rTie2+/+ mice but not Glp1rTie2–/– mice. Collectively, these findings demonstrate that Tie2+ endothelial or hematopoietic cell GLP-1Rs are dispensable for the antiatherogenic actions of GLP-1RA, whereas Tie2-targeted GLP-1R+ cells are required for a subset of the antiinflammatory actions of semaglutide in the liver.
Highlights
Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone secreted at low levels in the inter-prandial state, with circulating levels of GLP-1 rising briskly within minutes of meal ingestion [1, 2]
Our previous studies of atherosclerosis failed to demonstrate a clear reduction in aortic plaque burden in Apoe-/- mice treated with the long-acting Glucagon-like peptide-1 receptor agonists (GLP-1RA) taspoglutide [15]
Prior to undertaking more detailed studies of the GLP-1R and atherosclerosis using mouse genetics, we first investigated the effects of daily administration of liraglutide (Lira), a GLP-1RA shown to i) reduce experimental atherosclerosis in mice [16, 17] and ii) decrease major adverse cardiovascular events in humans [12]
Summary
Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone secreted at low levels in the inter-prandial state, with circulating levels of GLP-1 rising briskly within minutes of meal ingestion [1, 2]. Studies of GLP-1 action in animals and humans have demonstrated that GLP-1 decreases renal inflammation and albuminuria, reduces the extent of myocardial injury, attenuates the severity of experimental stroke, lowers blood pressure and postprandial lipemia, and exhibits anti-atherogenic activity in sensitized mouse models prone to the development of atherosclerosis [10]. These actions do not appear to be secondary to reduction of glycemia, as they have been detected in animals with normal glucose control
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