Related Experiment Video
Updated: Apr 17, 2026
An Experimental Model of Myocardial Infarction for Studying Cardiac Repair and Remodeling in Knockout Mice
Published on: July 14, 2023
Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction
Safina Ali1, John R Ussher2, Laurie L Baggio2
1Department of Laboratory Medicine and Pathobiology, Department of Medicine, Toronto, Ontario, Canada ; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON, Canada.
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 ex vivo, 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 Gcgr (CM-/-) mice significantly improved survival, and reduced hypertrophy and infarct size following myocardial infarction. Metabolic profiling of hearts from Gcgr (CM-/-) 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.
Insights
Glucagon receptor signaling in the heart impacts cardiac function and survival during ischemia. Inhibiting this pathway improves outcomes after heart attack, suggesting therapeutic potential for metabolic disorders.
Area of Science:
- Cardiovascular Physiology
- Metabolic Regulation
- Molecular Cardiology
Background:
- Glucagon is a key hormone for maintaining blood glucose levels.
- Targeting glucagon receptor (Gcgr) signaling is explored for diabetes and obesity.
- Cardiovascular effects of manipulating glucagon action are not well understood.
Purpose of the Study:
- To investigate the cardiovascular consequences of modulating glucagon receptor signaling.
- To assess the impact of cardiomyocyte Gcgr inactivation on cardiac function and survival following myocardial infarction.
Main Methods:
- Assessed infarct size, cardiac gene/protein expression, acylcarnitine profiles, and cardiomyocyte survival in wildtype and cardiomyocyte-specific Gcgr knockout mice after LAD ligation.
- Conducted complementary experiments on Gcgr signaling and cell survival in cardiomyocyte cultures and cell lines.
- Utilized p38 MAPK pathway analysis.
Main Results:
- Exogenous glucagon impaired recovery of ventricular pressure and increased mortality post-myocardial infarction via a p38 MAPK-dependent mechanism.
- Cardiomyocyte-specific Gcgr inactivation (Gcgr CM-/- mice) improved survival, reduced hypertrophy, and decreased infarct size.
- Gcgr CM-/- mice exhibited reduced long-chain acylcarnitines, indicating altered cardiac fatty acid utilization.
Conclusions:
- Modulating cardiac Gcgr signaling significantly impacts cardiac phenotypes in ischemic conditions.
- Findings have implications for developing therapeutic strategies targeting Gcgr signaling in metabolic disorders.
- Cardiac Gcgr plays a crucial role in regulating myocardial substrate utilization and response to ischemia.
