Metabolic Syndrome Abolishes Glucagon-Like Peptide 1 Receptor Agonist Stimulation of SERCA in Coronary Smooth Muscle.

Abstract

Metabolic syndrome (MetS) doubles the risk of adverse cardiovascular events. Glucagon-like peptide 1 (GLP-1) receptor agonists induce weight loss, increase insulin secretion, and improve glucose tolerance. Studies in healthy animals suggest cardioprotective properties of GLP-1 receptor agonists, perhaps partially mediated by improved sarco-endoplasmic reticulum Ca(2+) ATPase (SERCA) activity. We examined the acute effect of GLP-1 receptor agonists on coronary smooth muscle cells (CSM) enzymatically isolated from lean, healthy Ossabaw miniature swine. Intracellular Ca(2+) handling was interrogated with fura-2. The GLP-1 receptor agonist exenatide activated SERCA but did not alter other Ca(2+) transporters. Further, we tested the hypothesis that chronic, in vivo treatment with GLP-1 receptor agonist AC3174 would attenuate coronary artery disease (CAD) in swine with MetS. MetS was induced in 20 swine by 6 months' feeding of a hypercaloric, atherogenic diet. Swine were then randomized (n = 10/group) into placebo or AC3174 treatment groups and continued the diet for an additional 6 months. AC3174 treatment attenuated weight gain, increased insulin secretion, and improved glucose tolerance. Intravascular ultrasound and histology showed no effect of AC3174 on CAD. MetS abolished SERCA activation by GLP-1 receptor agonists. We conclude that MetS confers vascular resistance to GLP-1 receptor agonists, partially through impaired cellular signaling steps involving SERCA.

• Authors: Stacey L Dineen, Mikaela L McKenney, Lauren N Bell, Allison M Fullenkamp, Kyle A Schultz, Mouhamad Alloosh, Naga Chalasani, Michael Sturek
• Journal: Diabetes (Diabetes) Vol. 64 Issue 9 Pg. 3321-7 (Sep 2015) ISSN: 1939-327X [Electronic] United States
• PMID: 25845661 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• AC3174
• Blood Glucose
• Glucagon-Like Peptide-1 Receptor
• Insulin
• Peptides
• Receptors, Glucagon
• Venoms
• Exenatide
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Calcium

Topics

• Animals
• Blood Glucose (drug effects, metabolism)
• Calcium (metabolism)
• Coronary Artery Disease (diagnostic imaging, metabolism, pathology)
• Coronary Vessels (drug effects, metabolism)
• Diet, Atherogenic
• Exenatide
• Glucagon-Like Peptide-1 Receptor
• Insulin (metabolism)
• Insulin Secretion
• Metabolic Syndrome (metabolism)
• Muscle, Smooth, Vascular (drug effects, metabolism)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Peptides (pharmacology)
• Random Allocation
• Receptors, Glucagon (agonists)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (drug effects, metabolism)
• Swine
• Ultrasonography
• Venoms (pharmacology)
• Weight Loss (drug effects)