title: 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.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Dineen
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Mikaela L
authors.initials: ML
authors.lastname: McKenney
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Bell
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Fullenkamp
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Schultz
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Mouhamad
authors.initials: M
authors.lastname: Alloosh
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Naga
authors.initials: N
authors.lastname: Chalasani
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN msturek@iu.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Sturek
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D004036:Diet, Atherogenic; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D024821:Metabolic Syndrome / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D011897:Random Allocation; D018027:Receptors, Glucagon / Q000819:agonists*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects* / Q000378:metabolism; D013552:Swine; D014463:Ultrasonography; D014688:Venoms / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects
chemical_list: C553564:AC3174; D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
references.citation: Circulation. 2014 Jan 21;129(3):e28-e292
references.pmid: 24352519
references.citation: J Am Vet Med Assoc. 2001 Mar 1;218(5):669-96
references.pmid: 11280396
references.citation: Diabetes Care. 2004 Jan;27(1):256-63
references.pmid: 14693998
references.citation: Am J Physiol Endocrinol Metab. 2004 Dec;287(6):E1209-15
references.pmid: 15353407
references.citation: Circulation. 2005 Feb 8;111(5):583-90
references.pmid: 15699279
references.citation: Circ Res. 2005 Sep 2;97(5):488-95
references.pmid: 16081870
references.citation: Cell Metab. 2006 Mar;3(3):153-65
references.pmid: 16517403
references.citation: Neurochem Int. 2006 Jun;48(8):696-702
references.pmid: 16481070
references.citation: J Appl Physiol (1985). 2006 Sep;101(3):752-62
references.pmid: 16763107
references.citation: J Am Coll Cardiol. 2007 Jan 30;49(4):403-14
references.pmid: 17258085
references.citation: Regul Pept. 2007 Jun 7;141(1-3):113-9
references.pmid: 17292977
references.citation: J Am Coll Cardiol. 2009 Feb 10;53(6):501-10
references.pmid: 19195607
references.citation: Comp Med. 2010 Aug;60(4):300-15
references.pmid: 20819380
references.citation: Circ Cardiovasc Qual Outcomes. 2010 Sep;3(5):444-6
references.pmid: 20739707
references.citation: Cardiovasc Diabetol. 2010;9:76
references.pmid: 21080957
references.citation: J Appl Physiol (1985). 2011 Aug;111(2):573-86
references.pmid: 21596923
references.citation: Diabetes. 2012 Oct;61(10):2609-20
references.pmid: 22751695
references.citation: Eur J Pharmacol. 2013 Jan 15;699(1-3):106-11
references.pmid: 23220706
references.citation: Am J Physiol Cell Physiol. 2013 Mar;304(6):C508-18
references.pmid: 23302777
references.citation: Gene Ther. 2013 Apr;20(4):396-406
references.pmid: 22763406
references.citation: Basic Res Cardiol. 2013 Jul;108(4):365
references.pmid: 23764734