Abstract 13208: A Small Molecule Macrophage Migration Inhibitory Factor Agonist Ameliorates Age-Related Myocardial Intolerance to Ischemia-Reperfusion Insults via Metabolic Regulation

Abstract

Introduction: The macrophage migration inhibitory factor (MIF) is emerged as a critical mediator during myocardia ischemia and reperfusion (I/R). An impaired MIF signaling is occurred in aging. MIF agonist, MIF20, can argument cardiac MIF signaling through increasing the binding affinity between MIF and its receptor, CD74/CD44. Hypothesis: Administration of MIF20 can increase the resistance of aged myocardium to ischemic insults caused by I/R via modulating the MIF signaling regulated energy metabolism. Methods: Young (3-5 months) and aged (24-26 months) wild-type C57BL/6J mice, cardiomyocyte specific MIF knock out C57BL/6J mice (cMIF-/-) and wild type littermates (MIF flox/flox ) were injected with MIF20 (0.15 μg/kg, I.V.) 5 minutes before reperfusion after 45 minutes of ischemia. The left ventricular myocardium was for immunoblotting, NAD/NADH assay, and metabolomics analysis. The working heart perfusion and the SeaHorse system were for metabolic measurements. Results: The small molecule MIF agonist, MIF20, which binds to MIF to increase signaling through its cognate receptor CD74/CD44 not only decreases infarct size but also preserves cardiac systolic function in the aged versus young hearts. MIF20 contributes to the maintenance of mitochondrial fitness and preserves the contractility of cardiomyocytes under hypoxia and reoxygenation stress. These beneficial effects of MIF20 are reduced in cardiomyocyte-specific MIF knock-out (cMIF -/- ) versus littermates (MIF flox/flox ) mice, supporting the autocrine role of MIF in mediating ischemic cardiac protection. The age-related disruption of metabolic homeostasis in aged versus young hearts was modulated by MIF20’s ability to upregulate glucose oxidation and downregulate the oxidation of fatty acid. These actions were associated with an upregulation of pyruvate dehydrogenase kinase 4 (PDK4) and downregulation of Long-chain acyl-CoA dehydrogenase (LCAD). MIF20 as MIF signaling agonism modulation of metabolic adaptation in aged hearts further led to reduced generation of reactive oxygen species (ROS) in the myocardium. Conclusions: MIF agonists such as MIF20 may have a therapeutic role by limiting cardiac damage and rescuing cardiac dysfunctions of senescent hearts to I/R stress.