Cardioprotective and Vasodilatory Actions of Glucagon-Like Peptide 1 Receptor Are Mediated Through Both Glucagon-Like Peptide 1 Receptor–Dependent and –Independent Pathways

Abstract

Background-The glucagon-like peptide 1 receptor (GLP-1R) is believed to mediate glucoregulatory and cardiovascular effects of the incretin hormone GLP-1(7-36) (GLP-1), which is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) to GLP-1(9-36), a truncated metabolite generally thought to be inactive. Novel drugs for the treatment of diabetes include analogues of GLP-1 and inhibitors of DPP-4; however, the cardiovascular effects of distinct GLP-1 peptides have received limited attention. Methods and Results-Here, we show that endothelium and cardiac and vascular myocytes express a functional GLP-1R as GLP-1 administration increased glucose uptake, cAMP and cGMP release, left ventricular developed pressure, and coronary flow in isolated mouse hearts. GLP-1 also increased functional recovery and cardiomyocyte viability after ischemiareperfusion injury of isolated hearts and dilated preconstricted arteries from wild-type mice. Unexpectedly, many of these actions of GLP-1 were preserved in Glp1r Ϫ/Ϫ mice. Furthermore, GLP-1(9-36) administration during reperfusion reduced ischemic damage after ischemia-reperfusion and increased cGMP release, vasodilatation, and coronary flow in wild-type and Glp1r Ϫ/Ϫ mice, with modest effects on glucose uptake. Studies using a DPP-4 -resistant GLP-1R agonist and inhibitors of DPP-4 and nitric oxide synthase showed that the effects of GLP-1(7-36) were partly mediated by GLP-1(9-36) through a nitric oxide synthase-requiring mechanism that is independent of the known GLP-1R. Conclusions-These data describe cardioprotective actions of GLP-1(7-36) mediated through the known GLP-1R and novel cardiac and vascular actions of GLP-1(7-36) and its metabolite GLP-1(9-36) independent of the known GLP-1R. Our data suggest that the extent to which GLP-1 is metabolized to GLP-1(9-36) may have functional implications in the cardiovascular system.

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

“…To determine whether ER stress contributes to endothelial dysfunction in the setting of DM, we utilized liraglutide, a GLP‐1 analogue, which has been demonstrated to reduce ER stress in cultured endothelial cells exposed to high glucose17 and to exert favorable effects on cardiovascular function in both preclinical and clinical studies 18, 28, 29…”

“…Liraglutide is a GLP‐1 receptor agonist described to activate different signaling pathways via GLP‐1R‐dependent or independent signals 18. To determine if the effects of liraglutide on the vascular endothelium are mediated through GLP‐1R, freshly isolated endothelial cells from patients with DM were pretreated for 30 minutes with the GLP‐1R antagonist exendin fragment (9–39) before liraglutide and insulin sequential stimulation.…”

“…Experimental studies have demonstrated that the glucagon‐like peptide 1 (GLP‐1) receptor agonist, liraglutide, downregulates high glucose‐induced UPR activation and ER stress in cultured endothelial cells 17. Further, liraglutide improves cardiovascular function in animal models 18. However, limited translational research has addressed the involvement of ER stress activation in the vasculature, and the contribution of ER stress to endothelial dysfunction in human DM is not known.…”

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

“…Native glucagon‐like peptide‐1 (GLP‐1) is a hormone produced by the L‐cells of the distal ileum and colon in response to the entry of nutrients and destroyed by the circulating dipeptidyl peptidase‐4 (DPP‐4) (Ban et al., 2008). In the past decade, GLP‐1 and its analogs have been introduced as a new class of antidiabetic medications for their pleiotropic effects, including increasing glucose‐dependent insulin secretion, suppressing glucagon secretion, decreasing appetite, and reducing body weight (Park, Lim, Lee & Na, 2016).…”

“…A functional GLP‐1 receptor (GLP‐1R) is highly expressed in the heart. GLP‐1R agonists and DPP‐4 inhibitors have beneficial effects on the cardiovascular system (Ban et al., 2008; Noyan‐Ashraf et al., 2009; Timmers et al., 2009). Previous studies have shown that GLP‐1 and its analogs protected the heart against ischemia‐reperfusion injury and diabetes mellitus (Tate, Robinson, Green, McDermott & Grieve, 2016; Wang et al., 2013).…”