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

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. [Display omitted] •GIP does not impair ventricular function or survival after ischemic cardiac injury•Gain and loss of GIPR signaling regulates cardiac lipid metabolism•Selective elimination of the cardiomyocyte GIPR protects against ischemic injury•Cardiac GIPR expression is conserved in mouse and human ventricular cardiomyocytes 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.