Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection

John R. Ussher; Laurie L. Baggio; Jonathan E. Campbell; Erin E. Mulvihill; Minsuk Kim; M. Golam Kabir; Xiemin Cao; Benjamin M. Baranek; Doris A. Stoffers; Randy J. Seeley; Daniel J. Drucker

doi:10.1016/j.molmet.2014.04.009

Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection

John R. Ussher, Laurie L. Baggio, Jonathan E. Campbell, Erin E. Mulvihill, Minsuk Kim, M. Golam Kabir, Xiemin Cao, Benjamin M. Baranek, Doris A. Stoffers, Randy J. Seeley, Daniel J. Drucker

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

114 Scopus citations

Abstract

GLP-1R agonists improve outcomes in ischemic heart disease. Here we studied GLP-1R-dependent adaptive and cardioprotective responses to ventricular injury. Glp1r^-/- hearts exhibited chamber-specific differences in gene expression, but normal mortality and left ventricular (LV) remodeling after myocardial infarction (MI) or experimental doxorubicin-induced cardiomyopathy. Selective disruption of the cardiomyocyte GLP-1R in Glp1r^CM-/- mice produced no differences in survival or LV remodeling following LAD coronary artery occlusion. Unexpectedly, the GLP-1R agonist liraglutide still produced robust cardioprotection and increased survival in Glp1r^CM-/- mice following LAD coronary artery occlusion. Although liraglutide increased heart rate (HR) in Glp1r^CM-/- mice, basal HR was significantly lower in Glp1r^CM-/- mice. Hence, endogenous cardiomyocyte GLP-1R activity is not required for adaptive responses to ischemic or cardiomyopathic injury, and is dispensable for GLP-1R agonist-induced cardioprotection or enhanced chronotropic activity. However the cardiomyocyte GLP-1R is essential for the control of HR in mice.

Original language	English
Pages (from-to)	507-517
Number of pages	11
Journal	Molecular Metabolism
Volume	3
Issue number	5
DOIs	https://doi.org/10.1016/j.molmet.2014.04.009
State	Published - Aug 2014

Bibliographical note

Funding Information:
JRU was supported by fellowships from the Canadian Institutes of Health Research and the Alberta Innovates – Health Solutions . JEC has received fellowships from the Banting and Best Diabetes Centre, University of Toronto and the Canadian Institutes of Health Research. MK and EEM have received fellowships from the Canadian Diabetes Association . DJD has received operating grant support from the Heart and Stroke Foundation of Canada ( NA6997 ), from Novo Nordisk Inc , and is supported by a Canada Research Chair in Regulatory Peptides and a Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology.

Keywords

Cardiomyopathy
Glucagon-like peptide-1
Glucagon-like peptide-1 receptor
Heart failure
Incretin
Ischemia
Myocardial infarction

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10.1016/j.molmet.2014.04.009

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Ussher, J. R., Baggio, L. L., Campbell, J. E., Mulvihill, E. E., Kim, M., Kabir, M. G., Cao, X., Baranek, B. M., Stoffers, D. A., Seeley, R. J., & Drucker, D. J. (2014). Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection. Molecular Metabolism, 3(5), 507-517. https://doi.org/10.1016/j.molmet.2014.04.009

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title = "Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection",

abstract = "GLP-1R agonists improve outcomes in ischemic heart disease. Here we studied GLP-1R-dependent adaptive and cardioprotective responses to ventricular injury. Glp1r-/- hearts exhibited chamber-specific differences in gene expression, but normal mortality and left ventricular (LV) remodeling after myocardial infarction (MI) or experimental doxorubicin-induced cardiomyopathy. Selective disruption of the cardiomyocyte GLP-1R in Glp1rCM-/- mice produced no differences in survival or LV remodeling following LAD coronary artery occlusion. Unexpectedly, the GLP-1R agonist liraglutide still produced robust cardioprotection and increased survival in Glp1rCM-/- mice following LAD coronary artery occlusion. Although liraglutide increased heart rate (HR) in Glp1rCM-/- mice, basal HR was significantly lower in Glp1rCM-/- mice. Hence, endogenous cardiomyocyte GLP-1R activity is not required for adaptive responses to ischemic or cardiomyopathic injury, and is dispensable for GLP-1R agonist-induced cardioprotection or enhanced chronotropic activity. However the cardiomyocyte GLP-1R is essential for the control of HR in mice.",

keywords = "Cardiomyopathy, Glucagon-like peptide-1, Glucagon-like peptide-1 receptor, Heart failure, Incretin, Ischemia, Myocardial infarction",

author = "Ussher, {John R.} and Baggio, {Laurie L.} and Campbell, {Jonathan E.} and Mulvihill, {Erin E.} and Minsuk Kim and Kabir, {M. Golam} and Xiemin Cao and Baranek, {Benjamin M.} and Stoffers, {Doris A.} and Seeley, {Randy J.} and Drucker, {Daniel J.}",

note = "Funding Information: JRU was supported by fellowships from the Canadian Institutes of Health Research and the Alberta Innovates – Health Solutions . JEC has received fellowships from the Banting and Best Diabetes Centre, University of Toronto and the Canadian Institutes of Health Research. MK and EEM have received fellowships from the Canadian Diabetes Association . DJD has received operating grant support from the Heart and Stroke Foundation of Canada ( NA6997 ), from Novo Nordisk Inc , and is supported by a Canada Research Chair in Regulatory Peptides and a Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology. ",

year = "2014",

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doi = "10.1016/j.molmet.2014.04.009",

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Ussher, JR, Baggio, LL, Campbell, JE, Mulvihill, EE, Kim, M, Kabir, MG, Cao, X, Baranek, BM, Stoffers, DA, Seeley, RJ & Drucker, DJ 2014, 'Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection', Molecular Metabolism, vol. 3, no. 5, pp. 507-517. https://doi.org/10.1016/j.molmet.2014.04.009

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AU - Ussher, John R.

AU - Baggio, Laurie L.

AU - Campbell, Jonathan E.

AU - Mulvihill, Erin E.

AU - Kim, Minsuk

AU - Kabir, M. Golam

AU - Cao, Xiemin

AU - Baranek, Benjamin M.

AU - Stoffers, Doris A.

AU - Seeley, Randy J.

AU - Drucker, Daniel J.

N1 - Funding Information: JRU was supported by fellowships from the Canadian Institutes of Health Research and the Alberta Innovates – Health Solutions . JEC has received fellowships from the Banting and Best Diabetes Centre, University of Toronto and the Canadian Institutes of Health Research. MK and EEM have received fellowships from the Canadian Diabetes Association . DJD has received operating grant support from the Heart and Stroke Foundation of Canada ( NA6997 ), from Novo Nordisk Inc , and is supported by a Canada Research Chair in Regulatory Peptides and a Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology.

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N2 - GLP-1R agonists improve outcomes in ischemic heart disease. Here we studied GLP-1R-dependent adaptive and cardioprotective responses to ventricular injury. Glp1r-/- hearts exhibited chamber-specific differences in gene expression, but normal mortality and left ventricular (LV) remodeling after myocardial infarction (MI) or experimental doxorubicin-induced cardiomyopathy. Selective disruption of the cardiomyocyte GLP-1R in Glp1rCM-/- mice produced no differences in survival or LV remodeling following LAD coronary artery occlusion. Unexpectedly, the GLP-1R agonist liraglutide still produced robust cardioprotection and increased survival in Glp1rCM-/- mice following LAD coronary artery occlusion. Although liraglutide increased heart rate (HR) in Glp1rCM-/- mice, basal HR was significantly lower in Glp1rCM-/- mice. Hence, endogenous cardiomyocyte GLP-1R activity is not required for adaptive responses to ischemic or cardiomyopathic injury, and is dispensable for GLP-1R agonist-induced cardioprotection or enhanced chronotropic activity. However the cardiomyocyte GLP-1R is essential for the control of HR in mice.

AB - GLP-1R agonists improve outcomes in ischemic heart disease. Here we studied GLP-1R-dependent adaptive and cardioprotective responses to ventricular injury. Glp1r-/- hearts exhibited chamber-specific differences in gene expression, but normal mortality and left ventricular (LV) remodeling after myocardial infarction (MI) or experimental doxorubicin-induced cardiomyopathy. Selective disruption of the cardiomyocyte GLP-1R in Glp1rCM-/- mice produced no differences in survival or LV remodeling following LAD coronary artery occlusion. Unexpectedly, the GLP-1R agonist liraglutide still produced robust cardioprotection and increased survival in Glp1rCM-/- mice following LAD coronary artery occlusion. Although liraglutide increased heart rate (HR) in Glp1rCM-/- mice, basal HR was significantly lower in Glp1rCM-/- mice. Hence, endogenous cardiomyocyte GLP-1R activity is not required for adaptive responses to ischemic or cardiomyopathic injury, and is dispensable for GLP-1R agonist-induced cardioprotection or enhanced chronotropic activity. However the cardiomyocyte GLP-1R is essential for the control of HR in mice.

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KW - Glucagon-like peptide-1

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KW - Heart failure

KW - Incretin

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Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection

Abstract

Bibliographical note

Keywords

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