Abstract P102: The Role of Extracellular Signal-Regulated Kinase in Cardioprotective Effect of Macrophage Migration Inhibitory Factor
Background: Macrophage Migration Inhibitory Factor (MIF) has been certified as an important regulator in development of cardiovascular disease. We unveiled the role of cardiac MIF in limiting cardiac damages during ischemia. But the signaling mechanisms of MIF-mediated cardioprotection remain unclear. There are amount of evidence demonstrated that MIF stimulated extracellular signal-regulated kinase (ERK) signaling pathway, which plays a critical role in ischemic preconditioning. We hypothesize that MIF-ERK cascades may play an important role in mitigating cardiac injury during ischemia/reperfusion.
Methods and Results: In vivo regional ischemia was performed by occlusion of the left anterior descending (LAD) coronary artery in MIF knock out (MIF KO) mice and wild type (WT) littermates. The immunoblotting data demonstrated that ischemia/reperfusion (I/R) time-dependently stimulated ERK (Thr202/Tyr204) phosporlyation in both WT and MIF KO hearts, but the I/R-induced ERK activation was significantly impaired in MIF KO hearts compared to WT hearts (p<0.01). The dual staining data showed that MIF KO hearts displayed 2.3-fold greater infarct size than WT hearts followed by ischemia and reperfusion (p<0.05). Moreover, we measured the mechanical properties of isolated cardiomyocytes from WT and MIF KO hearts. The basal contractility of WT and MIF KO cardiomyocytes were similar, and hypoxia/reoxygenation (H/R) treatment depressed peak shortening (PS) and maximal velocity of shortening/relengthening (±dL/dt), and prolonged time-to-90% relengthening (TR90) in both WT and MIF KO cardiomyocytes. However, the cardiac depression by H/R was markedly stronger in MIF KO versus WT cardiomyocytes (all p<0.01), all of which were associated with blunted ERK activation by H/R in MIF KO cardiomyocytes (p<0.05 vs. WT). Furthermore, the specific inhibitor of ERK signaling pathway, U0126 (10 μM), significantly augmented H/R-induced cardiac dysfuction in WT cardiomyocytes (p<0.05 vs. H/R alone).
Conclusions: These data strongly suggest that cardiac MIF modulates the activation of ERK signaling pathway during ischemia/reperfusion. The MIF-ERK cascades play an important role in cardioprotection against myocardial I/R mediated injury.
This research has received full or partial funding support from the American Heart Association, National Center.