Abstract 13344: Cardiac Macrophage Migration Inhibitory Factor Activates Mitophagy to Prevent the Exacerbation of Pressure Overload-Induced Hypertrophic Cardiomyopathy in Mice
Background: Macrophage migration inhibitory factor (MIF) is cardioprotective against ischemia / reperfusion injury. Mitophagy is one of the subclasses of autophagy, selectively clearing off the dysfunctional mitochondria. Autophagy has been shown to protect against cardiac hypertrophy. The aim of this study was to evaluate the impact of MIF on pressure overload-induced cardiomyopathy and the underlying mechanism with a focus on AMPK-mTOR-dependent autophagy.
Methods: Wild-type and MIF knockout (MIF-/-) mice were subjected to abdominal aortic constriction or sham-operation and were maintained for 1 month. A cohort of MIF-/- mice was given the autophagy inducer rapamycin (i.p.) 1 week after the surgery for 3 weeks. Echocardiographic, cardiomyocyte mechanical function and intracellular calcium handling were assessed. Western blot was performed to examine cell signaling molecules expression. In the in vitro model, H9C2 cardiomyoblasts were challenged with phenylephrine (PE) in the presence and absence of MIF silencing or MIF reconstitution. Mitophagy was confirmed with triple staining (lysosome, mitochondria and LC3) and visualized under confocal microscope. Human idiopathic dilated cardiomyopathy (IDCM) LV samples were employed to study the expression of MIF and autophagy markers.
Results: MIF deficiency exacerbated pressure overload-induced hypertrophic cardiomyopathy and cardiac dysfunction in mice, associated with ablated cardiac autophagy activation. By facilitating autophagy activation, rapamycin negated the accentuated detrimental changes in MIF-/- mice whereas MIF reconstitution blocked unfavorable responses of MIF depletion using MIF siRNA in H9C2 exposed to PE. Inhibiting autophagy with 3-MA blocked the anti-hypertrophic effects of activating AMPK and inhibiting mTOR with AICAR and rapamycin, respectively. MIF depletion ablated PE-induced mitophagy activation in H9C2 cells. More importantly, increased expression of MIF and autophagy were seen concomitantly in human IDCM LV samples.
Conclusion: Our data suggest that MIF may be protective against exacerbated hypertrophy, through activation of mTOR-dependent mitophagy. Mitophagy induction may serve as a therapeutic avenue to improve cardiac function.
- © 2012 by American Heart Association, Inc.