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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

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 und... Full description

Journal Title: Endocrinology (Philadelphia) 2010-04, Vol.151 (4), p.1520-1531
Main Author: Ban, Kiwon
Other Authors: Kim, Kyoung-Han , Cho, Chan-Kyung , Sauvé, Meghan , Diamandis, Eleftherios P , Backx, Peter H , Drucker, Daniel J , Husain, Mansoor
Format: Electronic Article Electronic Article
Language: English
Subjects:
Abridged Index Medicus
Analysis of Variance
Animals
Biological and medical sciences
Blotting, Western
Cells, Cultured
Cytoprotection - drug effects
Dose-Response Relationship, Drug
Fundamental and applied biological sciences. Psychology
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
Vertebrates: endocrinology
Publisher: Chevy Chase, MD: Endocrine Society
ID: ISSN: 0013-7227
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recordid: cdi_proquest_miscellaneous_733803538
title: 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
format: Article
creator:
  • Ban, Kiwon
  • Kim, Kyoung-Han
  • Cho, Chan-Kyung
  • Sauvé, Meghan
  • Diamandis, Eleftherios P
  • Backx, Peter H
  • Drucker, Daniel J
  • Husain, Mansoor
subjects:
  • Abridged Index Medicus
  • Analysis of Variance
  • Animals
  • Biological and medical sciences
  • Blotting, Western
  • Cells, Cultured
  • Cytoprotection - drug effects
  • Dose-Response Relationship, Drug
  • Fundamental and applied biological sciences. Psychology
  • 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
  • Vertebrates: endocrinology
ispartof: Endocrinology (Philadelphia), 2010-04, Vol.151 (4), p.1520-1531
description: 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. The dipeptidyl peptidase-4-generated GLP-1 metabolite GLP-1(9-36)amide, but not the classical GLP-1R agonist exendin-4, exerts cytoprotective actions on human aortic endothelial cells and ventricular cardiac myocytes from Glp1r knockout mice.
language: eng
source:
identifier: ISSN: 0013-7227
fulltext: no_fulltext
issn:
  • 0013-7227
  • 1945-7170
url: Link


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titleGlucagon-Like Peptide (GLP)-1(9-36)Amide-Mediated Cytoprotection Is Blocked by Exendin(9-39) Yet Does Not Require the Known GLP-1 Receptor
creatorBan, Kiwon ; Kim, Kyoung-Han ; Cho, Chan-Kyung ; Sauvé, Meghan ; Diamandis, Eleftherios P ; Backx, Peter H ; Drucker, Daniel J ; Husain, Mansoor
creatorcontribBan, Kiwon ; Kim, Kyoung-Han ; Cho, Chan-Kyung ; Sauvé, Meghan ; Diamandis, Eleftherios P ; Backx, Peter H ; Drucker, Daniel J ; Husain, Mansoor
descriptionThe 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. The dipeptidyl peptidase-4-generated GLP-1 metabolite GLP-1(9-36)amide, but not the classical GLP-1R agonist exendin-4, exerts cytoprotective actions on human aortic endothelial cells and ventricular cardiac myocytes from Glp1r knockout mice.
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languageeng
publisherChevy Chase, MD: Endocrine Society
subjectAbridged Index Medicus ; Analysis of Variance ; Animals ; Biological and medical sciences ; Blotting, Western ; Cells, Cultured ; Cytoprotection - drug effects ; Dose-Response Relationship, Drug ; Fundamental and applied biological sciences. Psychology ; 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 ; Vertebrates: endocrinology
ispartofEndocrinology (Philadelphia), 2010-04, Vol.151 (4), p.1520-1531
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0Ban, Kiwon
1Kim, Kyoung-Han
2Cho, Chan-Kyung
3Sauvé, Meghan
4Diamandis, Eleftherios P
5Backx, Peter H
6Drucker, Daniel J
7Husain, Mansoor
title
0Glucagon-Like Peptide (GLP)-1(9-36)Amide-Mediated Cytoprotection Is Blocked by Exendin(9-39) Yet Does Not Require the Known GLP-1 Receptor
1Endocrinology (Philadelphia)
addtitleEndocrinology
descriptionThe 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. The dipeptidyl peptidase-4-generated GLP-1 metabolite GLP-1(9-36)amide, but not the classical GLP-1R agonist exendin-4, exerts cytoprotective actions on human aortic endothelial cells and ventricular cardiac myocytes from Glp1r knockout mice.
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0Abridged Index Medicus
1Analysis of Variance
2Animals
3Biological and medical sciences
4Blotting, Western
5Cells, Cultured
6Cytoprotection - drug effects
7Dose-Response Relationship, Drug
8Fundamental and applied biological sciences. Psychology
9Glucagon-Like Peptide 1 - administration & dosage
10Glucagon-Like Peptide 1 - analogs & derivatives
11Glucagon-Like Peptide 1 - metabolism
12Glucagon-Like Peptide-1 Receptor
13Heart - drug effects
14Male
15Mass Spectrometry
16Mice
17Mice, Knockout
18Myocardium - cytology
19Myocardium - metabolism
20Peptide Fragments - administration & dosage
21Peptide Fragments - metabolism
22Peptides - administration & dosage
23Peptides - metabolism
24Peptides - pharmacology
25Receptors, Glucagon - genetics
26Receptors, Glucagon - metabolism
27Recovery of Function
28Reperfusion Injury - drug therapy
29Signal Transduction - drug effects
30Time Factors
31Venoms - pharmacology
32Vertebrates: endocrinology
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0Ban, Kiwon
1Kim, Kyoung-Han
2Cho, Chan-Kyung
3Sauvé, Meghan
4Diamandis, Eleftherios P
5Backx, Peter H
6Drucker, Daniel J
7Husain, Mansoor
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titleGlucagon-Like Peptide (GLP)-1(9-36)Amide-Mediated Cytoprotection Is Blocked by Exendin(9-39) Yet Does Not Require the Known GLP-1 Receptor
authorBan, Kiwon ; Kim, Kyoung-Han ; Cho, Chan-Kyung ; Sauvé, Meghan ; Diamandis, Eleftherios P ; Backx, Peter H ; Drucker, Daniel J ; Husain, Mansoor
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0Abridged Index Medicus
1Analysis of Variance
2Animals
3Biological and medical sciences
4Blotting, Western
5Cells, Cultured
6Cytoprotection - drug effects
7Dose-Response Relationship, Drug
8Fundamental and applied biological sciences. Psychology
9Glucagon-Like Peptide 1 - administration & dosage
10Glucagon-Like Peptide 1 - analogs & derivatives
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12Glucagon-Like Peptide-1 Receptor
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15Mass Spectrometry
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17Mice, Knockout
18Myocardium - cytology
19Myocardium - metabolism
20Peptide Fragments - administration & dosage
21Peptide Fragments - metabolism
22Peptides - administration & dosage
23Peptides - metabolism
24Peptides - pharmacology
25Receptors, Glucagon - genetics
26Receptors, Glucagon - metabolism
27Recovery of Function
28Reperfusion Injury - drug therapy
29Signal Transduction - drug effects
30Time Factors
31Venoms - pharmacology
32Vertebrates: endocrinology
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1Kim, Kyoung-Han
2Cho, Chan-Kyung
3Sauvé, Meghan
4Diamandis, Eleftherios P
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1Kim, Kyoung-Han
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4Diamandis, Eleftherios P
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7Husain, Mansoor
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atitleGlucagon-Like Peptide (GLP)-1(9-36)Amide-Mediated Cytoprotection Is Blocked by Exendin(9-39) Yet Does Not Require the Known GLP-1 Receptor
jtitleEndocrinology (Philadelphia)
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issue4
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epage1531
pages1520-1531
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abstractThe 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. The dipeptidyl peptidase-4-generated GLP-1 metabolite GLP-1(9-36)amide, but not the classical GLP-1R agonist exendin-4, exerts cytoprotective actions on human aortic endothelial cells and ventricular cardiac myocytes from Glp1r knockout mice.
copChevy Chase, MD
pubEndocrine Society
pmid20172966
doi10.1210/en.2009-1197
oafree_for_read