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: Craig W Younce, Jianli Niu, Jennifer Ayala, Melissa A Burmeister, Layton H Smith, Pappachan Kolattukudy, Julio E Ayala
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 76 Pg. 172-6 (Nov 2014) ISSN: 1095-8584 [Electronic] England
• PMID: 25200599 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Cardiotonic Agents
• Ccl2 protein, mouse
• Chemokine CCL2
• Endoplasmic Reticulum Chaperone BiP
• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Hspa5 protein, mouse
• Inflammation Mediators
• Peptides
• Receptors, Glucagon
• Venoms
• Exenatide

Topics

• Animals
• Cardiotonic Agents (pharmacology)
• Cells, Cultured
• Chemokine CCL2 (genetics, metabolism)
• Drug Evaluation, Preclinical
• Endoplasmic Reticulum Chaperone BiP
• Exenatide
• Gene Expression
• Glucagon-Like Peptide-1 Receptor
• Hypertrophy, Left Ventricular (drug therapy, metabolism, physiopathology)
• Inflammation Mediators (metabolism)
• Male
• Mice, Transgenic
• Myocytes, Cardiac (metabolism)
• Peptides (pharmacology)
• Receptors, Glucagon (agonists)
• Stroke Volume
• Venoms (pharmacology)
• Ventricular Dysfunction (drug therapy, metabolism, physiopathology)