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

doi:10.1016/j.cmet.2017.11.003

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

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

52 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 language	English
Pages (from-to)	450-460.e6
Journal	Cell Metabolism
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2017.11.003
State	Published - 6 Feb 2018

Bibliographical note

Funding Information:
J.R.U. was supported by fellowships from the Canadian Institutes of Health Research (CIHR) and the Alberta Innovates-Health Solutions. J.E.C. has received fellowships from the Banting and Best Diabetes Centre (BBDC) and the CIHR. B.A.M. and H.E.B. received fellowships from the BBDC. H.E.B. received fellowship support from the Canadian Diabetes Association (CDA). S.A. has received a studentship from the BBDC. M.K. has received a fellowship from the CDA. E.E.M. has received fellowships from the CDA and the CIHR. D.J.D. has received funding from: the Heart and Stroke Foundation of Ontario G-14-0005953 , CIHR grants 82700 and 154321 , partial operating grant support from Merck for studies of cardiac GIP action, a Novo Nordisk postdoctoral training program grant, the Canada Research Chair in Regulatory Peptides, and a Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology. HL-1 cells were a generous gift from Dr. William Claycomb. Human heart tissue was provided via Dr. Kenneth B. Margulies at the University of Pennsylvania in Philadelphia, PA. We thank Chris Newgard and Olga Ilkayeva for helpful discussions surrounding analysis of cardiac metabolomics.

Funding Information:
J.R.U. has received a speaker's honorarium for symposia sponsored by Novo Nordisk. E.M. and J.C. have received a speaker's honorarium for symposia sponsored by Merck. Y.S. reports consulting or speaking fees from Novo Nordisk, MSD, Takeda Pharmaceuticals, Sanofi, Taisho Toyama Pharmaceuticals, Eli Lilly and Company, Mitsubishi Tanabe Pharma, Ono Pharmaceutical, Kowa, Astellas Pharma, and Boehringer Ingelheim.

Publisher Copyright:
© 2017 Elsevier Inc.

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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10.1016/j.cmet.2017.11.003

Cite this

Ussher, J. R., Campbell, J. E., Mulvihill, E. E., Baggio, L. L., Bates, H. E., McLean, B. A., Gopal, K., Capozzi, M., Yusta, B., Cao, X., Ali, S., Kim, M., Kabir, M. G., Seino, Y., Suzuki, J., & Drucker, D. J. (2018). Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction. Cell Metabolism, 27(2), 450-460.e6. https://doi.org/10.1016/j.cmet.2017.11.003

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title = "Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction",

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.",

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

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

note = "Funding Information: J.R.U. was supported by fellowships from the Canadian Institutes of Health Research (CIHR) and the Alberta Innovates-Health Solutions. J.E.C. has received fellowships from the Banting and Best Diabetes Centre (BBDC) and the CIHR. B.A.M. and H.E.B. received fellowships from the BBDC. H.E.B. received fellowship support from the Canadian Diabetes Association (CDA). S.A. has received a studentship from the BBDC. M.K. has received a fellowship from the CDA. E.E.M. has received fellowships from the CDA and the CIHR. D.J.D. has received funding from: the Heart and Stroke Foundation of Ontario G-14-0005953 , CIHR grants 82700 and 154321 , partial operating grant support from Merck for studies of cardiac GIP action, a Novo Nordisk postdoctoral training program grant, the Canada Research Chair in Regulatory Peptides, and a Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology. HL-1 cells were a generous gift from Dr. William Claycomb. Human heart tissue was provided via Dr. Kenneth B. Margulies at the University of Pennsylvania in Philadelphia, PA. We thank Chris Newgard and Olga Ilkayeva for helpful discussions surrounding analysis of cardiac metabolomics. Funding Information: J.R.U. has received a speaker's honorarium for symposia sponsored by Novo Nordisk. E.M. and J.C. have received a speaker's honorarium for symposia sponsored by Merck. Y.S. reports consulting or speaking fees from Novo Nordisk, MSD, Takeda Pharmaceuticals, Sanofi, Taisho Toyama Pharmaceuticals, Eli Lilly and Company, Mitsubishi Tanabe Pharma, Ono Pharmaceutical, Kowa, Astellas Pharma, and Boehringer Ingelheim. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

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doi = "10.1016/j.cmet.2017.11.003",

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Ussher, JR, Campbell, JE, Mulvihill, EE, Baggio, LL, Bates, HE, McLean, BA, Gopal, K, Capozzi, M, Yusta, B, Cao, X, Ali, S, Kim, M, Kabir, MG, Seino, Y, Suzuki, J & Drucker, DJ 2018, 'Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction', Cell Metabolism, vol. 27, no. 2, pp. 450-460.e6. https://doi.org/10.1016/j.cmet.2017.11.003

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T1 - Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction

AU - Ussher, John R.

AU - Campbell, Jonathan E.

AU - Mulvihill, Erin E.

AU - Baggio, Laurie L.

AU - Bates, Holly E.

AU - McLean, Brent A.

AU - Gopal, Keshav

AU - Capozzi, Megan

AU - Yusta, Bernardo

AU - Cao, Xiemin

AU - Ali, Safina

AU - Kim, Minsuk

AU - Kabir, M. Golam

AU - Seino, Yutaka

AU - Suzuki, Jinya

AU - Drucker, Daniel J.

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N2 - 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.

AB - 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.

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KW - cardiovascular

KW - diabetes

KW - glucose-dependent insulinotropic polypeptide

KW - gut peptide

KW - hormone sensitive lipase

KW - incretin

KW - ischemia

KW - myocardial infarction

KW - obesity

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ER -

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

Abstract

Bibliographical note

Keywords

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