Cardiac Function in Mice Lacking the Glucagon-Like Peptide-1 Receptor

Abstract

Glucagon-like peptide-1 (GLP-1) acts via its G protein-coupled receptor (GLP-1R) to regulate blood glucose. Although the GLP-1R is widely expressed in peripheral tissues, including the heart, and exogenous GLP-1 administration increases heart rate and blood pressure in rodents, the physiological importance of GLP-1R action in the cardiovascular system remains unclear. We now show that 2-month-old mice with genetic deletion of the GLP-1R (GLP-1R(-/-)) exhibit reduced resting heart rate and elevated left ventricular (LV) end diastolic pressure compared with CD-1 wild-type controls. At the age of 5 months, echocardiography and histology demonstrate increased LV thickness in GLP-1R(-/-) mice. Although baseline hemodynamic parameters of GLP-1R(-/-) did not differ significantly from those of wild type, GLP-1R(-/-) mice displayed impaired LV contractility and diastolic function after insulin administration. The defective cardiovascular response to insulin was not attributable to a generalized defect in the stress response, because GLP-1R(-/-) mice responded appropriately to insulin with increased c-fos expression in the hypothalamus and increased circulating levels of glucagon and epinephrine. Furthermore, LV contractility after exogenous epinephrine infusion was also reduced in GLP-1R(-/-) mice. These findings provide new evidence implicating an essential role for GLP-1R in the control of murine cardiac structure and function in vivo.

GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP

“…However, emerging evidence now indicates that this peptide hormone may have a number of additional effects on the cardiovascular system. Recent studies report wide-ranging cardiovascular actions of GLP-1 such as modulation of heart rate, blood pressure and cardiac structure and function [3][4][5][6][7][8]. Furthermore, GLP-1 has been shown to improve cardiovascular function in experimental heart failure [9,10] and in both diabetic and non-diabetic heart failure patients [11,12].…”

Small-molecule agonists for the glucagon-like peptide 1 receptor

“…Other effects include (i) growth, proliferation, and antiapoptosis of pancreatic ␤-cells and neogenesis from ductal precursor cells; (ii) glucosedependent lowering of glucagon secretion, leading to lower hepatic glucose output; (iii) inhibition of gastric acid secretion and gastric emptying, the latter causing a reduction in postprandial plasma glucose excursions; and (iv) inhibition of appetite and lowering of food intake leading to decreased body weight. New data also show GLP-1 to be both neuro-and cardioprotective (4,5). Because type 2 diabetes is characterized by a progressive decline in ␤-cell mass and function (6)(7)(8), increased glucagon secretion (9), and often is accompanied by severe obesity, GLP-1 seems ideal for its treatment.…”

A Recombinant Human Glucagon-Like Peptide (GLP)-1–Albumin Protein (Albugon) Mimics Peptidergic Activation of GLP-1 Receptor–Dependent Pathways Coupled With Satiety, Gastrointestinal Motility, and Glucose Homeostasis

“…Measurement of c-FOS activation in the murine CNS. The number of c-FOS immunoreactive neurons in specific brain regions was assessed quantitatively in both wild-type C57BL/6 and GLP-1R Ϫ/Ϫ mice as described (12,13). Briefly, animals were given IP injections of PBS, Ex-4, HSA, or Albugon in a 100 l volume.…”

“…Brains were removed immediately at the end of perfusion, kept in ice-cold 4% paraformaldehyde solution for 3 days, and then transferred to a solution containing paraformaldehyde and 10% sucrose for 12 h. Brains were cut into 25-m sections using a Leica SM2000R sliding microtome (Leica Microsystems, Richmond Hill, Ontario, Canada) and stored at Ϫ20°C in a cold cryoprotecting solution. Sections were processed for immunocytochemical detection of FOS using a conventional avidin-biotinimmunoperoxidase method (Vectastain ABC Elite Kit; Vector Laboratories, Burlingame, CA) as described (12). The FOS antibody (Sigma-Aldrich, Oakville, Ontario, Canada) was used at a 1:50,000 dilution.…”