Abstract 9886: A Differential role of Cardiac and Leukocyte derived Macrophage migration Inhibitory Factor in Facilitating Inflammatory Responses and Cardiac Remodeling post Myocardial Infarction
Inflammatory responses to myocardial infarction (MI) are essential for cardiac wound healing. However, excessive inflammation can lead to adverse cardiac remodeling and free wall ventricular rupture. We investigated whether Macrophage migration inhibitory factor (MIF); a pro-inflammatory cytokine, promotes inflammation and exacerbates cardiac injury following MI. MIF knockout (MIFKO) and Wild type (WT) mice were subjected to coronary artery occlusion to induce MI. Incidence of cardiac rupture within 1 week, was lower in MIFKO than WT mice (29% vs. 69%, median rupture day 5 vs. 4, p=0.002, n=29-39). MIFKO mice showed a lower density of CD45+ cellular infiltrates at day-3 (612 vs. 1213 cells/mm, n= 6-7), suppressed expression of IL-1β, MCP-1 and ICAM-1 (p<0.05, n= 6) at 24h, and lower MMP-9 and -2 activities at day-3 and day-7 by gelatin zymography (p<0.05 vs WT mice, n=5). Histology revealed reduced collagen deposition (48% vs. 59%) and increased infarct wall thickness (419 vs. 316 μm) in MIFKO hearts at day 14 post MI (both P<0.05, n=7-9) To differentiate the role of MIF derived from cardiomyocytes or leukocytes, we generated chimeric mice via bone marrow transplantation (BMT) i.e. WT mice received BMT from MIFKO mice (WTKO) and MIFKO mice received BMT from WT mice (KOWT). Compared to WTKO counterparts, KOWT mice post-MI presented a higher incidence of cardiac rupture (40% vs. 10%, median rupture day 10 vs. 9, p=0.003, n=38-45), a greater CD45+ cellular infiltration (p<0.05, n=7-8), reduced fractional shortening (16% vs. 25%) and enlarged ventricular diameter size measured by echocardiography (both p<0.05, n=11-21). Moreover, histological analysis demonstrated a larger fraction of the necrotic myocardium (30 vs. 18%, p<0.05), decreased collagen deposition (38 vs. 43%) and reduced infarcted wall thickness (245 vs. 344 μm) in KOWT than that in WTKO mice at day 7 and 14 post MI respectively (all p<0.05, n=7-9). MIF promotes inflammatory actions in the heart following MI. Global deletion of MIF protects the heart against acute cardiac remodelling and rupture via reduced inflammatory responses. Deletion of cardiac MIF delayed the onset of cardiac rupture while inflammatory cell derived MIF plays a crucial role in mediating post-MI cardiac remodelling.
- © 2012 by American Heart Association, Inc.