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
| العنوان: | 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 |
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| المؤلفون: | Mansoor Husain, Kyoung-Han Kim, Peter H. Backx, Daniel J. Drucker, Meghan Sauvé, Eleftherios P. Diamandis, Kiwon Ban, Chan-Kyung J Cho |
| المصدر: | Endocrinology. 151:1520-1531 |
| بيانات النشر: | The Endocrine Society, 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Male, Agonist, endocrine system, medicine.medical_specialty, Time Factors, medicine.drug_class, Blotting, Western, Biology, Glucagon-Like Peptide-1 Receptor, Mass Spectrometry, Mice, chemistry.chemical_compound, Endocrinology, Glucagon-Like Peptide 1, Internal medicine, Amide, Receptors, Glucagon, medicine, Animals, Receptor, Protein kinase B, Cells, Cultured, Glucagon-like peptide 1 receptor, Mice, Knockout, Analysis of Variance, Dose-Response Relationship, Drug, Venoms, Myocardium, digestive, oral, and skin physiology, Heart, Recovery of Function, Cytoprotection, Peptide Fragments, Nitric oxide synthase, chemistry, Reperfusion Injury, biology.protein, Exenatide, Signal transduction, Peptides, hormones, hormone substitutes, and hormone antagonists, Signal Transduction |
| الوصف: | 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. |
| تدمد: | 1945-7170 0013-7227 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::53969f09d8273698d4a3ad55c2f456b9Test https://doi.org/10.1210/en.2009-1197Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....53969f09d8273698d4a3ad55c2f456b9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19457170 00137227 |
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