Abstract 1004: Administration Of A Glucagon-like Peptide-1 Receptor Agonist Prevents Cardiac Rupture And Increases Survival In Mice Undergoing Myocardial Infarction
BACKGROUND: Glucagon-like peptide-1 (GLP-1) is a gut-derived hormone essential for regulation of glucose homeostasis. Although the GLP-1 receptor (GLP-1R) has been detected in the heart, the cellular distribution and function of the cardiac GLP-1R remains poorly understood.
OBJECTIVE: To examine the spatial pattern of GLP-1R expression and to ascertain whether GLP-1R activation produces cardioprotective effects in a mouse chronic LAD-occlusion model of myocardial infarction (MI).
METHODS & RESULTS: RT-PCR confirmed GLP-1R mRNA transcripts in different regions of the adult mouse heart. Western blot analysis revealed GLP-1R immunoreactive protein in homogenates from ventricles and atria. Confocal immunostaining revealed GLP-1R expression on cardiomyocytes, endothelial, endocardial and vascular smooth muscle cells, but not cardiac fibroblasts. Administration of a GLP-1R agonist twice daily for 7 days prior to LAD occlusion was associated with loss of abdominal fat, decreased weight (n = 60, Mean weight loss = 1.53 g, P = .0001) and significant cardio-protection, as evidenced by decreased infarct size (21.0 ± 1.7%, n = 36; vs. 28.8 ± 3.3%, n = 21; P = 0.02), cardiac rupture (12/60 vs. 46/60; P = 0.0001), and mortality (20% vs. 60%; P = 0.0001). Western blots pre- and 4 days post-MI revealed increased phosphorylation of pro-survival kinases Akt and GSK3β. Zymography 4 days post-MI showed a significant decrease in MMP-9 activity in the infarct zone of agonist-treated mice (P = 0.04).
CONCLUSIONS: Treatment with a GLP-1R agonist activates pro-survival kinases and reduces MMP9 expression in the mouse heart, which limits infarct size, expansion, and rupture.These findings may have implications for the use of GLP-1R agonists in the treatment of type 2 diabetes.