Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection.
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.
Ussher, JR; Baggio, LL; Campbell, JE; Mulvihill, EE; Kim, M; Kabir, MG; Cao, X; Baranek, BM; Stoffers, DA; Seeley, RJ; Drucker, DJ
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