Glucagon-like peptide-1 (GLP-1) mediates cardioprotection by remote ischaemic conditioning

Abstract

AimsAlthough the nature of the humoral factor which mediates cardioprotection established by remote ischaemic conditioning (RIc) remains unknown, parasympathetic (vagal) mechanisms appear to play a critical role. As the production and release of many gut hormones is modulated by the vagus nerve, here we tested the hypothesis that RIc cardioprotection is mediated by the actions of glucagon-like peptide-1 (GLP-1).Methods and resultsA rat model of myocardial infarction (coronary artery occlusion followed by reperfusion) was used. Remote ischaemic pre- (RIPre) or perconditioning (RIPer) was induced by 15 min occlusion of femoral arteries applied prior to or during the myocardial ischaemia. The degree of RIPre and RIPer cardioprotection was determined in conditions of cervical or subdiaphragmatic vagotomy, or following blockade of GLP-1 receptors (GLP-1R) using specific antagonist Exendin(9–39). Phosphorylation of PI3K/AKT and STAT3 was assessed. RIPre and RIPer reduced infarct size by ∼50%. In conditions of bilateral cervical or subdiaphragmatic vagotomy RIPer failed to establish cardioprotection. GLP-1R blockade abolished cardioprotection induced by either RIPre or RIPer. Exendin(9–39) also prevented RIPre-induced AKT phosphorylation. Cardioprotection induced by GLP-1R agonist Exendin-4 was preserved following cervical vagotomy, but was abolished in conditions of M3 muscarinic receptor blockade.ConclusionsThese data strongly suggest that GLP-1 functions as a humoral factor of remote ischaemic conditioning cardioprotection. This phenomenon requires intact vagal innervation of the visceral organs and recruitment of GLP-1R-mediated signalling. Cardioprotection induced by GLP-1R activation is mediated by a mechanism involving M3 muscarinic receptors.

Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning

“…Indeed, muscarinic antagonism, using atropine, abolished IPC-induced cardioprotection. The parasympathetic nervous system has a well-defined cardioprotective effect [34, 48, 49, 62], and recently emerged as a key mediator of the cardioprotection afforded by “remote” ischaemic conditioning (RIC) [6, 49, 55]. Indeed, a recent study demonstrated that increased parasympathetic tone ameliorated the functional and structural remodelling of the intrinsic cardiac nervous system following myocardial infarction [8].…”

Neuroprotection in Rats Following Ischaemia-Reperfusion Injury by GLP-1 Analogues—Liraglutide and Semaglutide

“…was administered 15 min before the injection of semaglutide (n = 8). The dose of Ex(9-39) was selected on the basis of our previous study [17]. Blood glucose was measured in three random rats in each group to make sure no significant decline of glucose concentration occurs in response to the administration of these drugs.…”

Heat shock protein 70: A promising therapeutic target for myocardial ischemia–reperfusion injury

“…For the mechanisms involved, RIPC‐induced cardioprotective effects are, at least in part, dependent on exosomes which significantly accumulate in the plasma during RIPC and subsequently alleviate myocardial I/R injury via their antiapoptotic properties (Minghua et al, ; Vicencio et al, ). In addition, other related mechanisms have been revealed, such as protein kinase C‐ε (PKC‐ε) overexpression (C. Wang et al, ), STAT5‐dependent antiapoptotic signaling pathway induction (H. Chen et al, ) and glucagon‐like peptide‐1 activation (Basalay et al, ).…”