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Effects of GLP‐1 receptor agonist on Ca2+ handling in coronary smooth muscle cells from metabolic syndrome Ossabaw swine with coronary artery disease
Author(s) -
Lee McKenney Mikaela,
Suh Daniel,
Martin John,
Alloosh Mouhamad,
Schultz Kyle,
Sturek Michael
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1195.5
Subject(s) - medicine , serca , endocrinology , coronary artery disease , exenatide , metabolic syndrome , endoplasmic reticulum , chemistry , type 2 diabetes , obesity , diabetes mellitus , atpase , biochemistry , enzyme
Chronic effects of glucagon‐like peptide (GLP‐1) receptor agonists were studied in Ossabaw swine with metabolic syndrome (MetS). MetS was induced by hypercaloric atherogenic diet for 6 months. Subcutaneous injections were given twice daily for 6 months after induction of MetS. Consistent with clinical effects, food consumption and weight gain were attenuated. MetS increases coronary artery disease (CAD) and coronary smooth muscle (CSM) Ca 2+ dysfunction. CSM cells were isolated enzymatically from the coronary arteries and Ca 2+ was digitally imaged with fluorescent fura‐2. In normal physiological salt solution we released sarcoplasmic reticulum (SR) stores with caffeine. Treated cells showed a larger Ca 2+ transient, ΔF360/380=0.26±0.02, compared to placebo cells, ΔF360/380=0.16±0.01 (p<0.001). In lean CSM, acute exposure to exenatide markedly increased activity of the sarcoplasmic‐endoplasmic reticulum Ca 2+ ATPase (SERCA). This activity was confirmed by cyclopizaonic acid block. The increased SERCA activity may explain increased SR Ca 2+ store in chronic MetS CSM. Acute exposure of placebo MetS CSM to exenatide has shown no effect on SERCA activity (n=43). Evidence for myocardial resistance to GLP‐1 in MetS is consistent with the lack of acute response. Our interpretation is that chronic exposure attenuates the decline in CSM Ca 2+ handling associated with more severe CAD and dedifferentiation of CSM. (Support: NIH HL062552 , TL1 TR000162 , Amylin Pharmaceuticals Inc.)