Interaction of MIF Family Proteins in Myocardial Ischemia/Reperfusion Damage and Their Influence on Clinical Outcome of Cardiac Surgery Patients

Abstract

Aims: Cardiac surgery involves myocardial ischemia/reperfusion (I/R) with potentially deleterious consequences. Macrophage migration inhibitory factor (MIF) is a stress-regulating chemokine-like cytokine that protects against I/R damage, but functional links with its homolog, d-dopachrome tautomerase (MIF-2), and the circulating soluble receptor CD74 (sCD74) are unknown. In this study, we investigate the role of MIF, MIF-2, sCD74, and MIF genotypes in patients scheduled for elective single or complex surgical procedures such as coronary artery bypass grafting or valve replacement. Results: MIF and MIF-2 levels significantly increased intraoperatively, whereas measured sCD74 decreased correspondingly. Circulating sCD74/MIF complexes were detectable in 50% of patients and enhanced MIF antioxidant activity. Intraoperative MIF levels were independently associated with a reduced risk for the development of atrial fibrillation (AF) (odds ratio 0.99 [0.98–1.00]; p=0.007). Circulating levels of MIF-2, but not MIF, were associated with an increased frequency of organ dysfunction and predicted the occurrence of AF (area under the curve [AUC]=0.663; p=0.041) and pneumonia (AUC=0.708; p=0.040). Patients with a high-expression MIF genotype exhibited a reduced incidence of organ dysfunction compared with patients with low-expression MIF genotypes (3 vs. 25; p=0.042). Innovation: The current study comprehensively highlights the kinetics and clinical relevance of MIF family proteins and the MIF genotype in cardiac surgery patients. Conclusion: Our findings suggest that increased MIF levels during cardiac surgery feature organ-protective properties during myocardial I/R, while the soluble MIF receptor, sCD74, may enhance MIF antioxidant activity. In contrast, high MIF-2 levels are predictive of the development of organ dysfunction. Importantly, we provide first evidence for a gene–phenotype relationship between variant MIF alleles and clinical outcome in cardiac surgery patients. Antioxid. Redox Signal. 00, 000–000.

MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics

“…Clinical outcomes were especially notable for acute kidney injury with a 5.5-fold increased incidence in low-genotypic MIF (−794 CATT 5/5 ) expressing patients. These human genetic data support the importance of MIF in tissue protection and suggest that therapeutic augmentation of MIF levels may be especially beneficial in those subjects who are low genotypic MIF expressers and more susceptible to ischemic complications [38]. …”

“…A circulating soluble form of CD74 (sCD74) also has been recently identified that appears to form by proteolytic truncation of the MIF binding ectodomain [35]. sCD74 binds MIF and transduces signal activity in vivo, and recent studies have implicated it in the clinical expression of autoimmune liver disease, acute lung injury, burn injury, and postoperative inflammatory responses [35, 36, 37, 38]. …”

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

“…Ectodomain shedding represents an important posttranslational modification event that downregulates cell‐surface expression of various receptors and liberates biologically active fragments that often exhibit a function that is distinct from that of the membrane‐bound receptor form 38. Although the effects of the intracellular domain of CD74, released following regulated intracellular proteolysis, have been extensively studied,39, 40, 41 we are only beginning to understand the functions of the CD74 ectodomain 37, 39, 42, 43, 44…”

Attenuated Recovery of Contractile Function in Aging Hearts Following Global Ischemia/Reperfusion: Role of Extracellular HSP27 and TLR4

“…It has been reported that global myocardial I/R induces an inflammatory response in human myocardium (10)(11)(12)(13)(14)34), and proinflammatory cytokines appear to play a role in cardiac complications associated with surgeries that obligate global myocardial I/R (17,18). Further, patients over age 65 suffer greater morbidity and mortality than younger cohorts following coronary artery bypass grafting or heart valve surgery.…”