Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis

Abstract

Short-term studies in subjects with diabetes receiving glucagon-like peptide 1 (GLP-1)-targeted therapies have suggested a reduced number of cardiovascular events. The mechanisms underlying this unexpectedly rapid effect are not known. We cloned full-length GLP-1 receptor (GLP-1R) mRNA from a human megakaryocyte cell line (MEG-01), and found expression levels of GLP-1Rs in MEG-01 cells to be higher than those in the human lung but lower than in the human pancreas. Incubation with GLP-1 and the GLP-1R agonist exenatide elicited a cAMP response in MEG-01 cells, and exenatide significantly inhibited thrombin-, ADP-, and collagen-induced platelet aggregation. Incubation with exenatide also inhibited thrombus formation under flow conditions in ex vivo perfusion chambers using human and mouse whole blood. In a mouse cremaster artery laser injury model, a single intravenous injection of exenatide inhibited thrombus formation in normoglycemic and hyperglycemic mice in vivo. Thrombus formation was greater in mice transplanted with bone marrow lacking a functional GLP-1R (Glp1r 2/2 ), compared with those receiving wild-type bone marrow. Although antithrombotic effects of exenatide were partly lost in mice transplanted with bone marrow from Glp1r 2/2 mice, they were undetectable in mice with a genetic deficiency of endothelial nitric oxide synthase. The inhibition of platelet function and the prevention of thrombus formation by GLP-1R agonists represent potential mechanisms for reduced atherothrombotic events.Type 2 diabetes (T2D) is associated with a number of risk factors that contribute to an increased risk of atherothrombotic events, including hypertension, dyslipidemia, obesity, and chronic inflammation, as well as endothelial and platelet dysfunction (1). Platelets are small, versatile, anucleate cells in the circulation that play critical roles in both early and late stages of atherothrombosis, contributing also to cell-based thrombin generation and blood coagulation (2). Subjects with T2D exhibit a prothrombotic state, including increased production of coagulation factors; decreased production of fibrinolytic factors; and a propensity to platelet activation, aggregation, and adhesion (1,3,4). Compounding the latter, subjects with T2D show reduced sensitivity to antiplatelet drugs, such as aspirin and clopidogrel (5,6), and manifest a higher incidence of cardiovascular events (1,6,7). Although the currently available antidiabetic agents have been effective at lowering blood glucose levels and preventing microvascular disease, until the recent EMPA-REG study (8), it had been exceedingly difficult to demonstrate the beneficial effects of normalizing blood glucose

Liraglutide in polycystic ovary syndrome: a randomized trial, investigating effects on thrombogenic potential

“…The effect of GLP-1 analogs on hemostasis has been studied in vitro and in animal models. Human megakaryocytes have been found to express GLP-1 receptors and both human and murine blood incubated with the GLP-1 analog exenatide have been found to have reduced in vitro thrombus formation (44). Arterial thrombus formation decreased in mice treated with i.v.…”

“…Arterial thrombus formation decreased in mice treated with i.v. exenatide, suggesting GLP-1 analogs to reduce platelet aggregation by inhibiting the release of α- and dense granules (44). Moreover, liraglutide has been shown to attenuate high-glucose-mediated PAI-1 expression in human endothelial cells (45).…”

Glucagon‐like peptide‐1 receptor signalling reduces microvascular thrombosis, nitro‐oxidative stress and platelet activation in endotoxaemic mice

“…Very recently, Cameron‐Vendrig et al ( demonstrated an inhibitory action of the GLP‐1 receptor agonist exenatide on platelet aggregation ex vivo and thrombus formation in animals. In accord with our data, they were able to detect the presence of the GLP‐1 receptor on platelets.…”

“…Further, Gupta et al ( demonstrated anti‐aggregatory effects of the DPP‐4 inhibitor sitagliptin on human platelets without providing the mechanism underlying this phenomenon. In a recent publication, Cameron‐Vendrig et al () provided evidence for platelet inhibition by the GLP‐1 receptor agonist exenatide leading to reduced thrombus formation in an animal model. The authors also showed that the anti‐aggregatory and anti‐thrombotic effects of exenatide were associated with increased levels of cAMP.…”

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

“…The available evidence, from publicly available transcriptome analyses such as the ImmGen (Immunological Genome) Project or from experimental studies in mice, localizes functional immune cell GLP-1R expression to a subset of intestinal intraepithelial lymphocytes (53). Similar challenges relate to interpretation of reports linking GLP-1R signaling to inhibition of platelet aggregation and reduced thrombosis in mice (54); notably, it is not yet clear from extensive transcriptomic analyses whether the canonical GLP-1R is expressed, detectable, and functional in mature platelets. Hence, more studies are needed of cells and tissues from animals and humans, ideally with experimental and clinical atherosclerosis and vascular dysfunction, to examine whether and how GLP-1 directly regulates immune cells or platelet biology through expression of the canonical GLP-1R.…”