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The MIF protein family in cardiac ischemia and heart failure: molecular mechanisms and translational avenues

Subject Area Anaesthesiology
Term from 2020 to 2025
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 443500595
 
Final Report Year 2025

Final Report Abstract

Background. The cytokine macrophage migration inhibitory factor (MIF) and its structural homolog D-dopachrome tautomerase (D-DT aka MIF-2) has recently gained attention for its complex role in cardiovascular disease and heart failure (HF) as well as cardiac surgery with its sequels. We and others demonstrated that MIF exerts early organoprotective effects in experimental (mouse) and clinical (human) settings of cardiac surgery, while it fuels inflammation in a later stage. MIF’s dual and complex activities are further manifested by the soluble form of its receptor CD74 (sCD74), which has been proposed as modulator limiting MIF’s proinflammatory downstream signalling activity. Recently – supported by an initial DFG grant - we were the first group that demonstrated that MIF and sCD74 synergistically induce programmed cell death and innate immunity in neonatal myofibroblast. Thus, we suggest that MIF protein family members represent promising targets to improve recovery after cardiac surgery and to modulate HF disease progression. Preclinical Part. Aim. We explored the potential of sCD74 as a modulator of cardiac inflammation and remodeling, which is of crucial relevance for patients after cardiac surgery. Findings. In adult cardiac myofibroblast, as a more clinically relevant model, we demonstrated decreased cell viability following MIF/sCD74 and MIF-2 (alone) treatment. In vivo, sCD74 transiently reduced cytokine levels in circulation of wildtype but not in Mif-deficient mice after acute myocardial infarction (AMI). Relevance. We are the first demonstrating that sCD74 limits MIF-mediated cytokine production in experimental AMI, indicating sCD74 as a promising therapeutic approach to limit systemic inflammation and resulting deleterious downstream effects. Translational Part. Aim. We aimed for unravelling the expression profile of the MIF protein family in human HF. Findings. The gene and protein expression of the MIF protein network is significantly different in nonfailing and failing hearts with reduced and preserved EF (HFrEF, HFpEF). We identified two distinct HFpEF subgroups with one exhibiting more pronounced rightsided heart dysfunction and strongly reduced expression of MIF and MIF-2. Accordingly, cardiac surgery patients with a CATTlow MIF promoter polymorphism (lowest MIF expressers) had a higher prevalence of HF. Relevance. Our findings position the MIF protein family as a central player in human HF pathophysiology, with diagnostic and potential therapeutic implications. Interdisciplinary highlights. Together with our cooperation partners we demonstrated that increased MIF levels are associated with worse outcome in critical and inflammatory diseases including cardiac, lung, and liver failure as well as hemorrhage. The MIF protein family is steadily increasing with the recent identification of plant MIF orthologs (MDLs). MDL1 that can synergistically interact with MIF and aggravate inflammation with a potential impact on human health.

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