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Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism

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Abstract

This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miRNA) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-minutes coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect the blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca2+ binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR-181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion.

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Acknowledgments

This work was supported by the National Institutes of Health grant, HL117620 (J. Tune and K. Mather, PI). Dr. Goodwill was supported by American Heart Association 13POST1681001813 (A. Goodwill, PI). Mr. Conteh was supported by National Institutes of Health HL117620-S1 (J. Tune and K. Mather, PI). Mr. Sassoon and Ms. Noblet were supported by grant number TL1 TR000162 (A. Shekhar, PI) from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. The authors also thank Arpad Somogyi and the Proteomics Core at The Ohio State University for performing protein extraction and mass spectrometry. The authors would also like to thank Jeanette McClintick and the Indiana University Center for Medical Genomics for performing miR microarrays. Ingenuity Pathway Analyses were made possible by a collaboration with WV-INBRE (supported by NIH Grant P20GM103434).

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  1. Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, USA

    Daniel J. Sassoon, Adam G. Goodwill, Jillian N. Noblet, Abass M. Conteh, B. Paul Herring & Johnathan D. Tune

  2. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, USA

    Jeanette N. McClintick

  3. Department of Medicine, Indiana University School of Medicine, 1120 W. Michigan St., Suite CL365, Indianapolis, IN, 46202, USA

    Kieren J. Mather

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  1. Daniel J. Sassoon
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Sassoon, D.J., Goodwill, A.G., Noblet, J.N. et al. Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism. Basic Res Cardiol 111, 43 (2016). https://doi.org/10.1007/s00395-016-0563-4

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