Signalling pathways activated by glucagon-like peptide-1 (7-36) amide in the rat heart and their role in protection against ischaemia.
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. I n 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.
MRC Cape Heart Centre and Department of Biomedical Sciences, Division of Physiology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg.
B
B
Huisamen
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S
Genade
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A
Lochner
D055372:AMP-Activated Protein Kinases; D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D038341:Glycogen Synthase Kinases / Q000378:metabolism; D006019:Glycolysis; D006339:Heart Rate; D066298:In Vitro Techniques; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010477:Perfusion; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D025481:Phosphofructokinase-2 / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
D055372:AMP-Activated Protein Kinases; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D052216:Glucagon-Like Peptide 1; D038341:Glycogen Synthase Kinases; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D025481:Phosphofructokinase-2; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C055453:glucagon-like peptide 1 (7-36)amide