Glucagon-like peptide (GLP)-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39) yet does not require the known GLP-1 receptor

Endocrinology. 2010 Apr;151(4):1520-31. doi: 10.1210/en.2009-1197. Epub 2010 Feb 19.


The widely expressed dipeptidyl peptidase-4 enzyme rapidly cleaves the gut hormone glucagon-like peptide-1 [GLP-1(7-36)amide] at the N terminus to generate GLP-1(9-36)amide. Both intact GLP-1(7-36)amide and GLP-1(9-36)amide exert cardioprotective actions in rodent hearts; however, the mechanisms underlying the actions of GLP-1(9-36)amide remain poorly understood. We used mass spectrometry of coronary effluents to demonstrate that isolated mouse hearts rapidly convert infused GLP-1(7-36)amide to GLP-1(9-36)amide. After ischemia-reperfusion (I/R) injury of isolated mouse hearts, administration of GLP-1(9-36)amide or exendin-4 improved functional recovery and reduced infarct size. The direct actions of these peptides were studied in cultured neonatal mouse cardiomyocytes. Both GLP-1(9-36)amide and exendin-4 increased levels of cAMP and phosphorylation of ERK1/2 and the phosphoinositide 3-kinase target protein kinase B/Akt. In I/R injury models in vitro, both peptides improved mouse cardiomyocyte viability and reduced lactate dehydrogenase release and caspase-3 activation. These effects were attenuated by inhibitors of ERK1/2 and phosphoinositide 3-kinase. Unexpectedly, the cardioprotective actions of GLP-1(9-36)amide were blocked by exendin(9-39) yet preserved in Glp1r(-/-) cardiomyocytes. Furthermore, GLP-1(9-36)amide, but not exendin-4, improved the survival of human aortic endothelial cells undergoing I/R injury, actions sensitive to the nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester (L-NAME). In summary, our findings demonstrate separate actions for GLP-1(9-36)amide vs. the GLP-1R agonist exendin-4 and reveal the existence of a GLP-1(9-36)amide-responsive, exendin(9-39)-sensitive, cardioprotective signaling pathway distinct from that associated with the classical GLP-1 receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Cytoprotection / drug effects*
  • Dose-Response Relationship, Drug
  • Exenatide
  • Glucagon-Like Peptide 1 / administration & dosage
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide-1 Receptor
  • Heart / drug effects
  • Male
  • Mass Spectrometry
  • Mice
  • Mice, Knockout
  • Myocardium / cytology
  • Myocardium / metabolism
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / metabolism*
  • Peptides / administration & dosage
  • Peptides / metabolism*
  • Peptides / pharmacology
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism*
  • Recovery of Function
  • Reperfusion Injury / drug therapy
  • Signal Transduction / drug effects
  • Time Factors
  • Venoms / pharmacology


  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Peptide Fragments
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • glucagon-like peptide-1 (9-36)-amide
  • exendin (9-39)
  • Glucagon-Like Peptide 1
  • Exenatide