Related Experiment Video
Updated: May 2, 2026
A Murine Closed-chest Model of Myocardial Ischemia and Reperfusion
Published on: July 17, 2012
Endothelial Cx40 limits myocardial ischaemia/reperfusion injury in mice
Sandrine Morel1, Vincent Braunersreuther, Marc Chanson
1Department of Pathology and Immunology, University of Geneva Medical School, CMU, Rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland.
Insights
Endothelial connexin 40 (Cx40) protects the heart from ischemia/reperfusion injury by activating the CD73 pathway. This Cx40-CD73 axis offers a potential therapeutic target for reducing reperfusion damage in coronary disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Immunology
Background:
- Gap junctions, formed by connexins (Cx), are crucial for cardiac function, mediating electrical coupling and cell-to-cell communication.
- Changes in connexin expression and function in cardiomyocytes are linked to myocardial infarction and reperfusion injury.
- The roles of endothelial connexins, specifically Cx40 and Cx37, in cardiac ischemia/reperfusion (IR) injury remain largely unknown.
Purpose of the Study:
- To investigate the role of endothelial connexins Cx40 and Cx37 in cardiac IR injury.
- To elucidate the underlying mechanisms, including the involvement of inflammatory responses and the CD73 pathway.
Main Methods:
- Utilized mice with endothelial-specific deletion of Cx40 (Cx40del) and Cx37-deficient mice.
- Assessed myocardial infarct size and neutrophil infiltration following 30 minutes of ischemia and 24 hours of reperfusion.
- Investigated the effects of methotrexate (a CD73 activator) and CD73 deficiency on cardiac IR injury.
Main Results:
- Endothelial-specific deletion of Cx40 significantly increased myocardial infarct size and neutrophil infiltration.
- Cx37 deficiency did not affect infarct size in this model.
- Methotrexate reduced infarct size and neutrophil infiltration in Cx40del mice, and CD73-deficient mice exhibited increased sensitivity to IR injury.
Conclusions:
- Endothelial Cx40, but not Cx37, plays a protective role against cardiac IR injury.
- This protective effect is mediated through the activation of the CD73 pathway.
- The Cx40-CD73 axis represents a promising therapeutic target for mitigating reperfusion damage in coronary artery disease.
Aims:
Gap junctions are indispensable for the function of heart and blood vessels by providing electrical coupling and direct cell-to-cell transfer of small signalling molecules. Gap junction channels between neighbouring cells are composed of 12 connexins (Cx). Changes in Cx43 expression, localization, and channel properties in cardiomyocytes contribute to infarction and reperfusion injury of the heart. It is increasingly recognized that deleterious consequences of ischaemia/reperfusion (IR) are modulated by the inflammatory response and endothelial function. The role of the endothelial connexins, i.e. Cx40 and Cx37, in cardiac IR injury is, however, not known.
Methods And Results:
Following 30 min ischaemia and 24 h reperfusion, we found a significant increase in myocardial infarct size in mice with endothelial-specific deletion of Cx40 (Cx40del), but not in Cx37-deficient mice. The cardioprotective effect of endothelial Cx40 was associated with a decrease in neutrophil infiltration. Moreover, beneficial effects of endothelial Cx40 were not observed in isolated Langendorff-perfused hearts, suggesting direct involvement of endothelial-leucocyte interactions in the cardiac injury. Single-dose administration of methotrexate, a CD73 activator, reduced infarct size and neutrophil infiltration into the infarcted myocardium in Cx40del but not in control mice. Similar to Cx40del mice, CD73-deficient mice showed increased sensitivity to cardiac IR injury, which could not be conversed by methotrexate.
Conclusion:
Endothelial Cx40, but not Cx37, is implicated in resistance of the heart to IR injury by activation of the CD73 pathway. Thus, the Cx40-CD73 axis may represent an interesting target for controlling reperfusion damage associated with revascularization in coronary disease.
