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

Cardiovasc Res. 2016 Dec;112(3):669-676. doi: 10.1093/cvr/cvw216. Epub 2016 Oct 4.


Aims: Although 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 results: A 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.

Conclusions: These 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.

Keywords: Cardioprotection; Glucagon-like peptide-1; Myocardial infarction; Myocardial ischaemia; Parasympathetic; Remote ischaemic conditioning; Reperfusion; Vagus nerve.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Exenatide
  • Femoral Artery / surgery*
  • Glucagon-Like Peptide 1 / antagonists & inhibitors
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide-1 Receptor / drug effects
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Hormone Antagonists / pharmacology
  • Ischemic Preconditioning / methods*
  • Ligation
  • Male
  • Muscarinic Antagonists / pharmacology
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / prevention & control*
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Peptide Fragments / pharmacology
  • Peptides / pharmacology
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M3 / drug effects
  • Receptor, Muscarinic M3 / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Vagotomy
  • Vagus Nerve / drug effects
  • Vagus Nerve / physiopathology*
  • Vagus Nerve / surgery
  • Venoms / pharmacology


  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Hormone Antagonists
  • Muscarinic Antagonists
  • Peptide Fragments
  • Peptides
  • Receptor, Muscarinic M3
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Venoms
  • exendin (9-39)
  • Glucagon-Like Peptide 1
  • Exenatide
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt