Abstract 13473: Macrophage Migration Inhibitory Factor Knockout Exacerbates Doxorubicin-Induced Cardiomyopathy: Role of Autophagy
Background: The cardioprotective function of macrophage migration inhibitory factor (MIF) against ischemia/reperfusion has been attributed to activation of AMPK pathway. Autophagy (activated or inhibited) has been shown to play a role in doxorubicin-induced cardiomyopathy. Rapamycin, an inhibitor of mTOR, is a widely accepted activator of autophagy. The aim of this study was to evaluate the role of MIF on doxorubicin-induced cardiomyopathy and the underlying signaling mechanism with a focus on autophagy.
Methods: Wild-type (WT) and MIF knockout (MIF-/-) mice were given saline or doxorubicin (10 mg/kg, i.p., at a 3-day interval, 20 mg/kg cumulative dose). A cohort of WT and MIF-/- mice was given rapamycin (6 mg/kg, i.p., at 2-day intervals, 3 injections) or rapamycin + doxorubicin for 1 week. Echocardiographic, cardiomyocyte contractile function and intracellular calcium handling were assessed. Western blot was performed to examine signaling mechanism involved.
Results: Our data revealed that doxorubicin elicited severe cardiomyopathy as evidenced by decreased fractional shortening, cardiomyocyte contractile dysfunction and intracellular Ca2+ mishandling, the effect of which was exacerbated by MIF knockout. MIF knockout significantly increased doxorubicin-induced mortality. The detrimental effect of doxorubicin was accompanied with disrupted cardiac autophagosome maturation, which was further exacerbated by MIF knockout. Activating autophagy with rapamycin partially rescued doxorubicin-induced cardiac dysfunction in WT mice. More importantly, rapamycin treatment dramatically attenuated doxorubicin-induced cardiac dysfunction in MIF-/- mice. In addition, rapamycin significantly decreased doxorubicin-induced mortality in WT and MIF-/- mice.
Conclusion: Our data suggest that MIF is cardioprotective against doxorubicin-induced cardiomyopathy. The underlying mechanism may be associated with facilitating autophagosome maturation disrupted by doxorubicin. By inhibiting mTOR and turning on autophagy, rapamycin may serve as a therapeutic tool to preserve cardiac function in patients under the treatment of doxorubicin.
- © 2012 by American Heart Association, Inc.