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Updated: Jun 27, 2026
Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration
Published on: May 24, 2016
MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo
Daniel J Lips1, Orlando F Bueno, Benjamin J Wilkins
1Department of Cardiology, Maastricht University, and Heart Lung Center Utrecht, Maastricht and Utrecht, Netherlands.
Background:
Myocardial infarction causes a rapid and largely irreversible loss of cardiac myocytes that can lead to sudden death, ventricular dilation, and heart failure. Members of the mitogen-activated protein kinase (MAPK) signaling cascade have been implicated as important effectors of cardiac myocyte cell death in response to diverse stimuli, including ischemia-reperfusion injury. Specifically, activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) has been associated with cardioprotection, likely through antagonism of apoptotic regulatory pathways.
Methods And Results:
To establish a causal relationship between ERK1/2 signaling and cardioprotection, we analyzed Erk1 nullizygous gene-targeted mice, Erk2 heterozygous gene-targeted mice, and transgenic mice with activated MEK1-ERK1/2 signaling in the heart. Although MEK1 transgenic mice were largely resistant to ischemia-reperfusion injury, Erk2+/- gene-targeted mice showed enhanced infarction areas, DNA laddering, and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick-end labeling (TUNEL) compared with littermate controls. In contrast, enhanced MEK1-ERK1/2 signaling protected hearts from DNA laddering, TUNEL, and preserved hemodynamic function assessed by pressure-volume loop recordings after ischemia-reperfusion injury.
Conclusions:
These data are the first to demonstrate that ERK2 signaling is required to protect the myocardium from ischemia-reperfusion injury in vivo.
Insights
Extracellular signal-regulated kinases 1/2 (ERK1/2) signaling is crucial for protecting the heart from damage caused by ischemia-reperfusion injury. Reduced ERK2 signaling increases heart damage, while enhanced signaling offers protection.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Signal Transduction
Background:
- Myocardial infarction leads to irreversible cardiac myocyte loss, causing heart failure.
- Mitogen-activated protein kinase (MAPK) pathways are key in cardiac myocyte death during ischemia-reperfusion.
- Extracellular signal-regulated kinases 1/2 (ERK1/2) activation is linked to cardioprotection by opposing apoptosis.
Purpose of the Study:
- To determine the causal role of ERK1/2 signaling in cardioprotection against ischemia-reperfusion injury.
- To investigate the in vivo effects of modulating MEK1-ERK1/2 pathway activity on cardiac function and survival.
Main Methods:
- Analysis of gene-targeted mice with altered Erk1 and Erk2 expression (Erk1 nullizygous, Erk2 heterozygous).
- Utilized transgenic mice with activated MEK1-ERK1/2 signaling in the heart.
- Assessed myocardial infarction size, DNA fragmentation (laddering), and TUNEL staining post-ischemia-reperfusion.
- Evaluated cardiac hemodynamic function using pressure-volume loop recordings.
Main Results:
- MEK1-ERK1/2 transgenic mice exhibited resistance to ischemia-reperfusion injury.
- Erk2+/- mice showed significantly larger infarction areas and increased DNA damage markers.
- Enhanced MEK1-ERK1/2 signaling prevented DNA fragmentation and preserved hemodynamic function.
Conclusions:
- This study provides the first in vivo evidence that ERK2 signaling is essential for myocardial protection.
- ERK2 signaling plays a critical role in mitigating cardiac damage following ischemia-reperfusion events.
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