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 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.
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
authors: John R
authors: JR
authors: Ussher
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
authors: Laurie L
authors: LL
authors: Baggio
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
authors: Jonathan E
authors: JE
authors: Campbell
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
authors: Erin E
authors: EE
authors: Mulvihill
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
authors: Minsuk
authors: M
authors: Kim
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
authors: M Golam
authors: MG
authors: Kabir
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
authors: Xiemin
authors: X
authors: Cao
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
authors: Benjamin M
authors: BM
authors: Baranek
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
authors: Doris A
authors: DA
authors: Stoffers
authors: UC College of Medicine, University of Cincinnati, Cincinnati, USA.
authors: Randy J
authors: RJ
authors: Seeley
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
authors: Daniel J
authors: DJ
authors: Drucker
keywords: Cardiomyopathy; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; Glucagon-like peptide-1; Glucagon-like peptide-1 receptor; HR, heart rate; Heart failure; Incretin; Ischemia; LAD, left anterior descending; MI, myocardial infarction; Myocardial infarction; tGLP-1, truncated forms of GLP-1 such as GLP-1(9–36) or GLP-1(28–36)