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

Mol Metab. 2014 May 9;3(5):507-17. doi: 10.1016/j.molmet.2014.04.009. eCollection 2014 Aug.

Affiliations

¹ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
² Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
³ UC College of Medicine, University of Cincinnati, Cincinnati, USA.

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.

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).