Glucagon Like Peptide-1 is Protective Against Myocardial Ischemia/Reperfusion Injury when Given Either as a Preconditioning Mimetic or at Reperfusion in an Isolated Rat Heart Model

Abstract

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.

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

“…Although evidence from multiple studies suggests that GLP-1 has important cardiovascular actions, 12,14,15,38,39 the mechanisms underlying these diverse effects have not been fully elucidated. Our results propose a novel 2-pathway schema for cardiovascular actions of GLP-1, one that depends on the GLP-1R for inotropic action, glucose uptake, ischemic preconditioning, and mild vasodilatory actions and the second that depends on rapid metabolism of GLP-1 to GLP-1 , the latter having GLP-1R-independent effects on postischemic recovery of cardiac function and vasodilation.…”

Cardioprotective effects of incretin during ischaemia-reperfusion

“…GLP-1 co-administered with DPP-4 inhibitor, valine pyrrolide (VP), could reduce the infarct size ranging from 39% to 58% in isolated Langendorff rat hearts whether given prior to ischaemia or during the reperfusion period. [26][27][28][29] However, the administration of GLP-1 28 or DPP-4 inhibitor 26-28 alone failed to reduce the infarct size. These studies suggested the synergistic effect of DPP-4 inhibition and exogenous GLP-1 on the infarct limiting effect in which DDP-4 inhibitor enhanced endogenous GLP-1 level and reduced exogenous GLP-1 degradation.…”

“…48,53 However, some studies demonstrated that prolonged availability of intact GLP-1 caused by a DPP-4 inhibitor failed to demonstrate the infarct limiting effect. [26][27][28]54 Moreover, inhibition or reduction of DPP-4 activity using DPP-4 deleted mice or pretreatment with sitagliptin before ischaemia in high fat diet-induced diabetic mice could not reduce the infarct size, but improved the survival rate by activation of cardioprotection kinase such as GSK3β, ANP and Akt. 49 These discrepant results suggest that the different animal models, the duration of ischaemia in the heart models and the minimal dose for a specific time may play a pivotal role in the reduction of the infarct size.…”

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“…16 In addition to this chronotropic effect, a positive inotropic effect also has been attributed to direct myocardial activity. Recent evidence suggests that GLP-1 may enhance recovery of left ventricular function after transient coronary artery occlusion in an isolated rat heart model, 17,18 possibly mediated through insulin-like activity in improving glucose uptake by cardiomyocytes 17 and through the activation antiapoptotic signaling pathways shown to protect against myocardial injury. 19 A similar benefit has been demonstrated in conscious dogs with pacing-induced cardiomyopathy.…”