Summary of Research

Microphage migration inhibitory factor (MIF) as an innate cytokine that plays a pleiotropic role in both facilitating inflammation and modulating cellular metabolism in the heart. We reported that autocrine MIF exerts a protective effect on ischemic myocardium by re-modeling metabolic profile of cardiomyocytes therefore improve the resistance to reperfusion damage. This effect attenuates in the senescent heart however due to reduced expression and secretion of MIF by aged cardiomyocytes. We hypothesized that treating the aged heart with the MIF agonist, MIF20, to augment the effect of MIF signaling cascade in cardiomyocytes can improve the aged heart tolerance to ischemic reperfusion (I/R) stress. Results from a mouse I/R model show that the small molecule MIF agonist, MIF20, which binds to MIF to increase signaling through its cognate receptor CD74 not only decreases infarct size in but also preserves cardiac systolic function in the aged heart. MIF20 contributes to maintaining mitochondrial fitness and preserves the contractility of cardiomyocytes under stress. These beneficial effects of MIF20 are reduced in cardiomyocyte-specific MIF knock-out mice, supporting the theory that autocrine MIF mediates cardiac protection under I/R stress. The age-related disruption of metabolic homeostasis in aged hearts was re-modeled by MIF20 regarding to upregulate glucose oxidation and downregulate the oxidation of fatty acid. The metabolic profile alterations are associated with an upregulation of PDK4 and downregulation of LCAD. MIF20 modulation of metabolic adaptation in aged hearts further led to reduced generation of reactive oxygen species (ROS) in the myocardium. Further studies will be focus on investigating the transducing signaling molecules inside cell and identify more features of MIF20 effects in aged hearts.