Abstract 1136: Role of Glucagon-Like Peptide-1 in Myocardial Ischemia-Reperfusion Injury
GLP-1 is a member of the gut incretin hormone family, and its receptor agonist Exendin-4 is approved for the treatment of Type-2 diabetes. Studies in humans post-MI, and rat and dog models suggest that GLP-1 is cardioprotective. However, the mechanisms underlying these effects have not been fully elucidated.
Methods & Results: To examine acute and direct effects of GLP-1 in an ischemia reperfusion (I/R)-induced cardiac injury in C57Bl6 mice (wt) and mice lacking the GLP-1 receptor (GLP1r−/−) in the C57Bl6 background, LV developed pressure (LVDP) was measured in Krebs-Hens buffer-perfused isolated Langendorff preparations. Recovery of LV function after 20 min of either pre or post treatment of GLP-1 and analogues were assessed during 30 min of global ischemia followed by 40 min of reperfusion. In wt, recovery of LVDP following I/R was higher in both GLP-1 (0.3nM) and Exendin-4 (5nM) pre-infused hearts (79±9% and 75±7%, n=4 – 6, respectively) than in untreated controls (26±1%, n=15; p<0.01). However, the protective effect afforded by Exendin-4 was blunted by co-treatment with the GLP-1r antagonist, Exendin(9–39) (5nM: 49±3%, n=3; p<0.05). Although pre-infusion of GLP(9 –36), a metabolized form of GLP-1 believed to be biologically inactive, induced lower recovery than in untreated controls (11±1%, n=7; p<0.01), post-infusion of GLP(9 –36) or GLP-1 augmented functional recovery (69±8% and 70±6%, n=4). Of note, marked increases in coronary flow were detected in normoxic hearts during GLP(9 –36) infusion (8.4±0.4 vs. 11.2±0.8AU, p<0.05). Surprisingly, cardioprotective effects from pre-treatment of both GLP-1 and Exendin-4 remained evident in GLP-1r−/− hearts (77.4±6.2% and 70.8±8.6%, n=4, respectively)
Summary: These data suggest that the beneficial effects of GLP-1 infusions observed in humans post-MI and in animal models are mediated in part by direct protection from I/R injury. These data are the first to suggest an effect of GLP-1 on coronary flow, and highlight the intriguing possibility of signaling mechanisms independent of the GLP-1r.