Cardioprotective Effect of Glucagon Like Peptide-1 Receptor During Reperfusion of Isolated Ischemic Rat Heart Involves AMP-Activated Protein Kinase (AMPK) and Akt Signaling Pathways

Adenosine monophosphate-activated protein kinase (AMPK) and Akt are two important pathways playing a pivotal role in the survival of cardiomyocytes during ischemia-reperfusion through their energy preserving and antiapoptotic actions. These two pathways were reported to be stimulated by the incretin peptide glucagon like peptide-1 in liver and pancreas respectively by a glucagon-like peptide-1 receptor (GLP-1 R) dependent mechanism. GLP-1 R is also found in the heart and is shown to exert cardiovascular effects in a number of experimental models, however, the mechanisms whereby it couples to intracellular effectors in the heart, remain largely unexplored. This study investigated the possi-bility that postconditioning with exendin-4 (Exe 4), a degra-dation resistant peptide agonist at GLP-1R, could protect the heart against I/R injury via AMPK and Akt signaling pathways. Isolated rat hearts were randomly divided into control (con-tinuously perfused), I/R (30min ischemia and 2h reperfusion), I/R-Exe 4, I/R Exe 9-39 (GLP-1 R blocker) and I/R- Exe4+Exe 9-39 groups. When administered, the agents were only present for the first 20min of a 120min reperfusion period (postcon-ditioning protocol). Left ventricular performance (left ventric-ular developed pressure (LVDP), contractility index (dpldt) and rate pressure product) was assessed. Creatine kinase in cardiac perfusate and nitrite, pAMPkinase and pakt were measured in the heart tissue. Exe-4, was able to significantly improve I/R-induced impairment in left ventricular perfor-mance (LVDP, dp/dt and rate-pressure product) and signifi-cantly decreased creatine kinase release after 2h of reperfusion which was abolished by exendin (9-39) the GLP-1R antagonist. I/R induced activation of AMPK in all I/R groups compared to control group. Exe 4 through GLP-1R stimulation beneficially activated the left ventricle AMPK and Akt signaling and increased left ventricle nitrite as an index of nitric oxide production in I/R-Exe 4 group compared to the control and the other I/R groups.In conclusion post-ischemic stimulation of heart GLP-1 R during reperfusion enhanced left ventricular recovery, activated AMPK and Akt and increased nitric oxide production which may provide new insight into therapeutic strategies for the treatment of I/R injury.