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

Research output: Contribution to journalArticlepeer-review

105 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 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.

Original languageEnglish
Pages (from-to)507-517
Number of pages11
JournalMolecular Metabolism
Volume3
Issue number5
DOIs
StatePublished - 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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