Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction

John R. Ussher, Jonathan E. Campbell, Erin E. Mulvihill, Laurie L. Baggio, Holly E. Bates, Brent A. McLean, Keshav Gopal, Megan Capozzi, Bernardo Yusta, Xiemin Cao, Safina Ali, Minsuk Kim, M. Golam Kabir, Yutaka Seino, Jinya Suzuki, Daniel J. Drucker

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr −/− mice was partially reversed by pharmacological activation or genetic overexpression of HSL. Selective Gipr inactivation in cardiomyocytes phenocopied Gipr −/− mice, resulting in improved survival and reduced adverse remodeling following experimental MI. Hence, the cardiomyocyte GIPR regulates fatty acid metabolism and the adaptive response to ischemic cardiac injury. These findings have translational relevance for developing GIPR-based therapeutics. Ussher et al. demonstrate that the GIP receptor is expressed in cardiomyocytes and that direct activation of GIPR signaling regulates cardiac lipid metabolism. GIPR agonism was not deleterious in the context of ischemic cardiac injury; however, germline- or cardiomyocyte-selective loss of GIPR signaling increased survival and reduced adverse ventricular remodeling.

Original languageEnglish
Pages (from-to)450-460.e6
JournalCell Metabolism
Volume27
Issue number2
DOIs
StatePublished - 6 Feb 2018

Keywords

  • G-protein-coupled receptor
  • cardiovascular
  • diabetes
  • glucose-dependent insulinotropic polypeptide
  • gut peptide
  • hormone sensitive lipase
  • incretin
  • ischemia
  • myocardial infarction
  • obesity

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