Abstract 13868: Macrophage Migration Inhibitory Factor Deficiency Exacerbates Aging-induced Cardiac Dysfunction in Mice: Role of Autophagy
Background: As a proinflammatory cytokine, macrophage migration inhibitory factor (MIF) has been demonstrated to play an indispensable role in the maintenance of cardiac homeostasis under various pathological conditions. Autophagy is an evolutionarily conserved pathway for bulk degradation of intracellular proteins and organelles. The aim of this study was to evaluate the impact of MIF on cardiac aging and the underlying mechanism with a focus on mTOR-dependent autophagy.
Methods: Both young (5-month-old) and aged (24-month-old) wild-type (WT) and MIF knockout (MIF-/-) mice were used. To examine the effect of autophagy induction on cardiac aging, a cohort of young (3-mo) and aged (22-mo) WT and MIF-/- mice was given the autophagy inducer rapamycin (i.p., 2 mg/kg/d) for 2 mo. Echocardiographic, cardiomyocyte mechanical and intracellular calcium handling properties were assessed. Western blot was performed to examine cell signaling molecules expression. In the in vitro model, H9C2 cardiomyoblasts were challenged with doxorubicin (1 μg/ml, 24 hrs) to induce premature senescence to further evaluate the role of MIF and autophagy in senescence.
Results: MIF deficiency exacerbated aging-induced cardiac geometric and functional alterations in mice, associated with a more pronounced cardiac autophagy inhibition. With facilitated autophagy activation, rapamycin effectively negated the unfavorable myocardial changes in aged WT and MIF-/- mice. MIF reconstitution reversed doxorubicin-induced unfavorable responses of MIF depletion using MIF siRNA in H9C2 cells. Treatment with rapamycin attenuated the detrimental effect of MIF depletion in doxorubicin-induced premature senescence in H9C2 cells, the effect of which was mitigated by autophagy inhibition with 3-MA.
Conclusion: Our data suggest that MIF is an indispensable in the maintenance of cardiac geometry and function in aging process, probably through governing myocardial autophagy activity. Our findings implicated a potential therapeutic strategy for autophagy induction in the management of cardiac aging.
- © 2013 by American Heart Association, Inc.