Signalling pathways activated by glucagon-like peptide-1 (7-36) amide in the rat heart and their role in protection against ischaemia

SUMMARY: Glucagon-like peptide-1 is an incretin hormone proposed to have insulinomimetic effects on peripheral insulin-sensitive tissue. We examined these effects on the heart by using isolated, perfused rat hearts and adult ventricular myocytes. During normoxic perfusion, no effects of escalating concentrations of GLP-1 on either heart rate or left ventricular developed pressure were found. With functional performance as readout, we found that GLP-1 directly protected the heart against damage incurred by global low-flow ischaemia. This protection was sensitive to the presence of iodo-acetate, implicating activation of glycolysis, and was abolished by wortmannin, indicative of PI-3-kinase as mediator of protection. In addition, GLP-1 had an infarct-sparing effect when supported by the presence of the dipeptidyl peptidase-IV inhibitor valine pyrrolidide. GLP-1 could not directly activate protein kinase B (also called Akt) or the extracellular regulated kinases Erk1/2 in hearts or cardiocytes under normoxic conditions, but phosphorylation of the AMP-activated kinase (AMPK) on Thr(172) was enhanced. In addition, the glycolytic enzyme phosphofructokinase-2 was activated dose dependently. During reperfusion after ischaemia, modulation of the phosphorylation of PKB/Akt as well as AMPK was evident. GLP-1 therefore directly protected the heart against low-flow ischaemia by enhancing glycolysis, probably via activation of AMP kinase and by modulating the profile of activation of the survival kinase PKB/Akt.