title: Exendin-4 improves cardiac function in mice overexpressing monocyte chemoattractant protein-1 in cardiomyocytes.
abstract: The incretin hormone glucagon-like peptide-1 (Glp1) is cardioprotective in models of ischemia-reperfusion injury, myocardial infarction and gluco/lipotoxicity. Inflammation is a factor in these models, yet it is unknown whether Glp1 receptor (Glp1r) agonists are protective against cardiac inflammation. We tested the hypothesis that the Glp1r agonist Exendin-4 (Ex4) is cardioprotective in mice with cardiac-specific monocyte chemoattractant protein-1 overexpression. These MHC-MCP1 mice exhibit increased cardiac monocyte infiltration, endoplasmic reticulum (ER) stress, apoptosis, fibrosis and left ventricular dysfunction. Ex4 treatment for 8 weeks improved cardiac function and reduced monocyte infiltration, fibrosis and apoptosis in MHC-MCP1 mice. Ex4 enhanced expression of the ER chaperone glucose-regulated protein-78 (GRP78), decreased expression of the pro-apoptotic ER stress marker CCAAT/-enhancer-binding protein homologous protein (CHOP) and increased expression of the ER calcium regulator Sarco/Endoplasmic Reticulum Calcium ATPase-2a (SERCA2a). These findings suggest that the Glp1r is a viable target for treating cardiomyopathies associated with stimulation of pro-inflammatory factors.
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL 32827, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Younce
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
authors.forename: Jianli
authors.initials: J
authors.lastname: Niu
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL 32827, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ayala
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL 32827, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Burmeister
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL 32827, USA.
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
authors.forename: Pappachan
authors.initials: P
authors.lastname: Kolattukudy
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL 32827, USA. Electronic address: jayala@sanfordburnham.org.
authors.forename: Julio E
authors.initials: JE
authors.lastname: Ayala
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D000091342:Endoplasmic Reticulum Chaperone BiP; D000077270:Exenatide; D015870:Gene Expression; D000067757:Glucagon-Like Peptide-1 Receptor; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists; D013318:Stroke Volume; D014688:Venoms / Q000494:pharmacology*; D018754:Ventricular Dysfunction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D002316:Cardiotonic Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D000091342:Endoplasmic Reticulum Chaperone BiP; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; C000717248:Hspa5 protein, mouse; D018836:Inflammation Mediators; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide
keywords: Cardiomyopathy; Exendin-4; Glucagon-like peptide-1; Inflammation; Monocyte chemoattractant protein-1