The role of MIF in myocardial ischemic preconditioning

• Applicants: Professor Dr. Jürgen Bernhagen; Professor Dr. Christian Stoppe
• Subject Area: Anaesthesiology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280719815

Cytokines are well-characterized mediators in the immune response, which are known to be involved in the development and progression of cardiovascular diseases. Macrophage migration inhibitory factor (MIF) belongs to the first cytokines that has been discovered. It is a structurally unique inflammatory cytokine with chemokine-like activities that acts as a key mediator of the innate and acquired immune response. MIF is an upstream regulator of the initial immune response that initiates and exacerbates various chronic and acute inflammatory disorders such as atherosclerosis and sepsis. Detrimental effects of MIF on the heart such as induction of apoptosis in cardiomyocytes and contractile dysfunction in sepsis have been previously observed. In contrast, increasing evidence suggests a time-dependent dual mode of action of MIF during prolonged hypoxia and/or myocardial ischemia/reperfusion (I/R), respectively. In fact, emerging evidence suggests an overall cardioprotective role of MIF within the clinical setting of I/R that becomes in particular relevant for patients with myocardial infarction or for those patients that undergo cardiac surgery. In this context, we already provided first evidence about the significance of perioperative MIF release on the occurrence of organ dysfunctions in cardiac surgical patients with following myocardial I/R. To date, several protective mechanisms and signaling pathways have been identified to provide MIF mediated cardioprotection during ischemia and reperfusion in the heart. Preconditioning has repeatedly been shown to be a powerful strategy to effect myocardial protection against ischemia. This phenomenon establishes a transient protective cellular state in the myocardium by complex and multiple fast-acting signaling steps lasting for few hours. Given the fact that MIF-induced cardioprotective effects are comparable in nature to those that have been identified for ischemic-induced preconditioning and our own preliminary findings that indicated an association between preconditioning-induced MIF release and the activation of the cardioprotective kinases, demonstrate the need for a more comprehensive investigation about the functional role of MIF in preconditioning. Since ischemic preconditioning belongs to the rare promising preservation strategies, which are known to confer cardioprotection, we aim to investigate the functional role of MIF in the underlying pathways. We predict to be able to reveal the potential role of this pleiotropic cytokine in the complex interplay in preconditioning and to discover potential factors, which might influence the extent of MIF secretion in patients exposed to myocardial I/R.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Cooperation Partner: Professor Derek Yellon, Ph.D.