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Updated: Aug 30, 2026
A Modified Simple Method for Induction of Myocardial Infarction in Mice
Published on: December 3, 2021
Calcineurin Abeta gene targeting predisposes the myocardium to acute ischemia-induced apoptosis and dysfunction
Orlando F Bueno1, Daniel J Lips, Robert A Kaiser
1Department of Pediatrics, Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Insights
The study reveals that calcineurin-NFAT signaling protects the heart from apoptosis during ischemia-reperfusion injury. Loss of calcineurin Abeta in mice led to increased cardiac cell death and impaired function.
Area of Science:
- Cardiology
- Molecular Biology
- Cellular Biology
Background:
- Cardiovascular disease, particularly coronary heart disease (CHD), is a major cause of death globally.
- Acute myocardial infarction leads to significant loss of heart muscle via apoptosis and necrosis.
- The role of calcineurin (PP2B) in cardiac apoptosis following ischemia-reperfusion injury requires elucidation.
Purpose of the Study:
- To investigate the function of calcium calmodulin-activated protein phosphatase calcineurin (PP2B) in modulating cardiac apoptosis after ischemia-reperfusion injury.
- To determine the impact of calcineurin Abeta deficiency on myocardial viability and cardiac function post-injury.
- To explore the underlying molecular mechanisms, including gene expression changes and the involvement of the NFAT pathway.
Main Methods:
- Utilized calcineurin Abeta gene-targeted mice and wild-type controls subjected to ischemia-reperfusion injury.
- Assessed myocardial viability using DNA laddering and TUNEL assays.
- Performed RNA expression profiling and utilized NFAT-luciferase reporter transgenic mice to analyze gene expression and pathway activity.
Main Results:
- Calcineurin Abeta knockout mice exhibited greater myocardial loss, enhanced apoptosis markers, and reduced functional performance compared to controls.
- RNA profiling revealed a generalized downregulation of gene expression in calcineurin Abeta knockout hearts.
- NFAT-luciferase reporter assays showed reduced NFAT activity in knockout hearts, while NFAT activation protected against apoptosis.
Conclusions:
- Calcineurin-NFAT signaling plays a critical prosurvival role in the heart during ischemia-reperfusion injury.
- Genetic loss of calcineurin Abeta impairs the heart's ability to withstand ischemic stress, leading to increased cell death.
- These findings highlight calcineurin-NFAT as a potential therapeutic target for cardioprotection.
Abstract:
Cardiovascular disease is the leading cause of mortality and morbidity within the industrialized nations of the world, with coronary heart disease (CHD) accounting for as much as 66% of these deaths. Acute myocardial infarction is a typical sequelae associated with long-standing coronary heart disease resulting in large scale loss of ventricular myocardium through both apoptotic and necrotic cell death. In this study, we investigated the role that the calcium calmodulin-activated protein phosphatase calcineurin (PP2B) plays in modulating cardiac apoptosis after acute ischemia-reperfusion injury to the heart. Calcineurin Abeta gene-targeted mice showed a greater loss of viable myocardium, enhanced DNA laddering and TUNEL, and a greater loss in functional performance compared with strain-matched wild-type control mice after ischemia-reperfusion injury. RNA expression profiling was performed to uncover potential mechanisms associated with this loss of cardioprotection. Interestingly, calcineurin Abeta-/- hearts were characterized by a generalized downregulation in gene expression representing approximately 6% of all genes surveyed. Consistent with this observation, nuclear factor of activated T cells (NFAT)-luciferase reporter transgenic mice showed reduced expression in calcineurin Abeta-/- hearts at baseline and after ischemia-reperfusion injury. Finally, expression of an activated NFAT mutant protected cardiac myocytes from apoptotic stimuli, whereas directed inhibition of NFAT augmented cell death. These results represent the first genetic loss-of-function data showing a prosurvival role for calcineurin-NFAT signaling in the heart.
