Glucagon-like peptide 1 (GLP-1), a gut incretin hormone that stimulates insulin secretion, also activates antiapoptotic signaling pathways such as phosphoinositide 3-kinase and mitogen-activated protein kinase in pancreatic and insulinoma cells. Since these kinases have been shown to protect against myocardial injury, we hypothesized that GLP-1 could directly protect the heart against such injury via these prosurvival signaling pathways. Both isolated perfused rat heart and whole animal models of ischemia/reperfusion were used, with infarct size measured as the end point of injury. In both studies, GLP-1 added before ischemia demonstrated a significant reduction in infarction compared with the valine pyrrolidide (an inhibitor of its breakdown) or saline groups. This protection was abolished in the in vitro hearts by the GLP-1 receptor antagonist exendin
GLP-1 alone did not decrease myocardial infarction (54.4 +/- 3.1%). VP alone did not decrease myocardial infarction (52.5 +/- 4%). GLP-1 in the presence of VP produced significant reduction in myocardial infarction compared to control hearts (28.4 +/- 2.7% vs. 56.4 +/- 3.9% vs. P < 0.05). Inhibiting p70s6 Kinase with rapamycin completely abolished GLP-1 induced protection (57.1 +/- 4.9% vs. 28.4 +/- 2.7% P < 0.05). There was no detectable increase in the phosphorylated p70s6k after either 5 or 10 min of treatment with GLP-1/VP or with VP alone in comparison to control blots. In conclusion we show for the first time that the protective effects of GLP-1 are mediated by intact GLP-1 and can be inhibited by blocking the p70s6 kinase.
A number of recent studies have identified potential beneficial effects for Glucagon Like Peptide-1 (GLP-1), a potent gut incretin hormone with notable cell regulatory and anti-apoptotic actions predominantly in the pancreas [1]. However, recent studies have not only identified receptors for GLP-1 in the myocardium [2] but also demonstrated its beneficial roles in cardiac physiology and metabolism. Investigators reported improved left ventricular performance and reduced stunning in both clinical and experimental studies [3]. In animal models, it was demonstrated that an activation of glycolysis [4] as well as a decrease in pyruvate and lactate [5] occur in the myocardium when GLP-1 is given prior to ischemia. We have recently shown GLP-1 protects the myocardium by reducing infarct size [6] in both an in vitro and in vivo rat heart model, when the agent was given throughout ischemia and reperfusion. This protective effect was mediated by GLP-1 receptor activation in addition to activation of the prosurvival kinases PI3K/Akt, p44/42 and PKA [6].Since it is known that activation of the above kinases form part of the so-called Reperfusion Injury Salvage Kinase pathway (RISK pathway) [7], which is also associated with both preconditioning protection [8] as well as protection against reperfusion injury [7] we hypothesised that since GLP-1 has the ability to activate these kinases, it may protect against infarction when given either before ischemia (as a preconditioning mimetic) or at reperfusion. MethodsMale Sprague-Dawley rats hearts (n = 6/group) were retrogradelly perfused in a constant pressure system. The experimental protocol consisted of 35 min regional ischemia followed by 120 min reperfusion. The end point was the measurement of infarct size (using TTC staining) developed within the risk zone (using Evans blue dye), expressed as a percentage of the area at risk (I/R%). Native sequenced human GLP-1 (0.3 nM, Novo Nordisk, Denmark) and valine pyrolidide (VP-20 mg/L, Novo Nordisk, Denmark), an inhibitor of GLP-1 breakdown, were dissolved in perfusion buffer. The hearts were randomly distributed in the following groups: (a) control hearts (35 min ischemia, 120 min reperfusion); (b) preconditioned hearts (2 times 5 min global normothermic ischemia interspaced with 10 min reperfusion before the 35 min lethal ischemia and 120 min reperfusion); (c) hearts pre-treated with GLP-1 (and VP) for 15 min followed by washout for 5 min prior to ischemia/reperfusion insult; (d) hearts treated with GLP-1 (and VP) for the first 15 min of reperfusion. (e)-(f) hearts treated only with VP prior to ischemia (as in group c) or at reperfusion (as in group d).All results are expressed as mean ±SEM. Infarct size was analysed by factorial ANOVA. Differences were considered significant when p < 0.05.
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