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Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction

Publication ,  Journal Article
Ali, S; Ussher, JR; Baggio, LL; Kabir, MG; Charron, MJ; Ilkayeva, O; Newgard, CB; Drucker, DJ
Published in: Molecular Metabolism
February 1, 2015

Objective: Glucagon is a hormone with metabolic actions that maintains normoglycemia during the fasting state. Strategies enabling either inhibition or activation of glucagon receptor (Gcgr) signaling are being explored for the treatment of diabetes or obesity. However, the cardiovascular consequences of manipulating glucagon action are poorly understood. Methods: We assessed infarct size and the following outcomes following left anterior descending (LAD) coronary artery ligation; cardiac gene and protein expression, acylcarnitine profiles, and cardiomyocyte survival in normoglycemic non-obese wildtype mice, and in newly generated mice with selective inactivation of the cardiomyocyte Gcgr. Complementary experiments analyzed Gcgr signaling and cell survival in cardiomyocyte cultures and cell lines, in the presence or absence of exogenous glucagon. Results: Exogenous glucagon administration directly impaired recovery of ventricular pressure in ischemic mouse hearts exvivo, and increased mortality from myocardial infarction after LAD coronary artery ligation in mice in a p38 MAPK-dependent manner. In contrast, cardiomyocyte-specific reduction of glucagon action in adult GcgrCM-/- mice significantly improved survival, and reduced hypertrophy and infarct size following myocardial infarction. Metabolic profiling of hearts from GcgrCM-/- mice revealed a marked reduction in long chain acylcarnitines in both aerobic and ischemic hearts, and following high fat feeding, consistent with an essential role for Gcgr signaling in the control of cardiac fatty acid utilization. Conclusions: Activation or reduction of cardiac Gcgr signaling in the ischemic heart produces substantial cardiac phenotypes, findings with implications for therapeutic strategies designed to augment or inhibit Gcgr signaling for the treatment of metabolic disorders.

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Published In

Molecular Metabolism

DOI

EISSN

2212-8778

Publication Date

February 1, 2015

Volume

4

Issue

2

Start / End Page

132 / 143

Related Subject Headings

  • 3101 Biochemistry and cell biology
  • 0606 Physiology
  • 0601 Biochemistry and Cell Biology
 

Citation

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Ali, S., Ussher, J. R., Baggio, L. L., Kabir, M. G., Charron, M. J., Ilkayeva, O., … Drucker, D. J. (2015). Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction. Molecular Metabolism, 4(2), 132–143. https://doi.org/10.1016/j.molmet.2014.11.005
Ali, S., J. R. Ussher, L. L. Baggio, M. G. Kabir, M. J. Charron, O. Ilkayeva, C. B. Newgard, and D. J. Drucker. “Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction.” Molecular Metabolism 4, no. 2 (February 1, 2015): 132–43. https://doi.org/10.1016/j.molmet.2014.11.005.
Ali S, Ussher JR, Baggio LL, Kabir MG, Charron MJ, Ilkayeva O, et al. Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction. Molecular Metabolism. 2015 Feb 1;4(2):132–43.
Ali, S., et al. “Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction.” Molecular Metabolism, vol. 4, no. 2, Feb. 2015, pp. 132–43. Scopus, doi:10.1016/j.molmet.2014.11.005.
Ali S, Ussher JR, Baggio LL, Kabir MG, Charron MJ, Ilkayeva O, Newgard CB, Drucker DJ. Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction. Molecular Metabolism. 2015 Feb 1;4(2):132–143.
Journal cover image

Published In

Molecular Metabolism

DOI

EISSN

2212-8778

Publication Date

February 1, 2015

Volume

4

Issue

2

Start / End Page

132 / 143

Related Subject Headings

  • 3101 Biochemistry and cell biology
  • 0606 Physiology
  • 0601 Biochemistry and Cell Biology