Related Experiment Video
Updated: Jun 18, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion
Dake Qi1, Xiaoyue Hu, Xiaohong Wu
1Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Abstract:
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that also modulates physiologic cell signaling pathways. MIF is expressed in cardiomyocytes and limits cardiac injury by enhancing AMPK activity during ischemia. Reperfusion injury is mediated in part by activation of the stress kinase JNK, but whether MIF modulates JNK in this setting is unknown. We examined the role of MIF in regulating JNK activation and cardiac injury during experimental ischemia/reperfusion in mouse hearts. Isolated perfused Mif-/- hearts had greater contractile dysfunction, necrosis, and JNK activation than WT hearts, with increased upstream MAPK kinase 4 phosphorylation, following ischemia/reperfusion. These effects were reversed if recombinant MIF was present during reperfusion, indicating that MIF deficiency during reperfusion exacerbated injury. Activated JNK acts in a proapoptotic manner by regulating BCL2-associated agonist of cell death (BAD) phosphorylation, and this effect was accentuated in Mif-/- hearts after ischemia/reperfusion. Similar detrimental effects of MIF deficiency were observed in vivo following coronary occlusion and reperfusion in Mif-/- mice. Importantly, excess JNK activation also was observed after hypoxia-reoxygenation in human fibroblasts homozygous for the MIF allele with the lowest level of promoter activity. These data indicate that endogenous MIF inhibits JNK pathway activation during reperfusion and protects the heart from injury. These findings have clinical implications for patients with the low-expression MIF allele.
Insights
Macrophage migration inhibitory factor (MIF) protects the heart from reperfusion injury by inhibiting the JNK pathway. MIF deficiency exacerbates cardiac damage and cell death, highlighting its protective role.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cell Signaling
Background:
- Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with known roles in cardiac physiology.
- MIF limits cardiac injury during ischemia by enhancing AMPK activity.
- The role of MIF in modulating JNK activation during cardiac reperfusion injury was previously unknown.
Purpose of the Study:
- To investigate the role of MIF in regulating JNK activation and cardiac injury during experimental ischemia/reperfusion.
- To determine if MIF deficiency exacerbates cardiac damage and if MIF administration mitigates this injury.
Main Methods:
- Utilized isolated perfused mouse hearts (Mif-/- vs. WT) subjected to ischemia/reperfusion.
- Assessed cardiac function, necrosis, and JNK pathway activation (including MAPK kinase 4 phosphorylation).
- Administered recombinant MIF during reperfusion and examined effects in vivo and in human fibroblasts with varying MIF promoter activity.
Main Results:
- Mif-/- hearts exhibited greater contractile dysfunction, necrosis, and JNK activation post-reperfusion compared to WT hearts.
- Recombinant MIF administration reversed the exacerbated injury in Mif-/- hearts.
- MIF deficiency accentuated JNK-mediated proapoptotic signaling (BAD phosphorylation) and detrimental effects were observed in vivo and in human cells with low MIF expression.
Conclusions:
- Endogenous MIF inhibits JNK pathway activation during cardiac reperfusion, thereby protecting the heart from injury.
- MIF deficiency exacerbates ischemia/reperfusion-induced cardiac damage.
- These findings suggest clinical implications for patients carrying low-expression MIF alleles.
