Abstract 11730: Endogenous MAFbx Mediates Cardiac Rupture After Myocardial Infarction in Mice
Rationale: Muscle atrophy F-box (MAFbx/atrogin-1), an E3 ubiquitin ligase, plays a critical role in mediating skeletal muscle atrophy and induces proteasomal degradation in cardiomyocytes. Loss of function of MAFbx inhibits pressure overload-induced pathological cardiac hypertrophy, in part through stabilization of IκB. The role of MAFbx in regulating cardiac remodeling following myocardial infarction (MI) remains unclear.
Objective: We investigated the role of MAFbx in regulating cardiac remodeling following MI.
Methods and Results: Permanent coronary ligation of the left coronary artery was applied to MAFbx knockout (KO) and wild-type (WT) mice. Expression of MAFbx in WT mice was significantly increased in the risk area of the LV after MI. The mortality rate due to cardiac rupture following MI was significantly decreased in MAFbx KO mice compared to WT mice (25.3% in KO mice (n=61) vs. 47.7% in WT mice (n=59) P=0.03). There was no difference in the infarct sizes 3 days after MI or the number of TUNEL-positive cardiomyocytes between MAFbx KO mice and WT mice. DNA microarray analyses revealed that the gene expression pattern in hearts after MI demonstrated clear clusters for MAFbx KO and WT. Interestingly, upregulation of matrix metalloproteinase (MMP)-9, interleukin 1β, proinflammatory cytokines, and NLRP3, an inflammasone component, were attenuated in MAFbx KO mice. MMP-9 activity was also decreased in MAFbx KO in the risk area 3 days after MI compared to in WT mice. Flow cytometry revealed that myocardial leukocyte infiltration one day after MI was suppressed in MAFbx KO mice. Immunofluorescence double-labeling showed that expression of NLRP3 in both cardiomyocytes and non-cardiomyocyte cells was decreased in MAFbx KO mice.
Conclusions: These results suggest that MAFbx plays an important role in the excessive inflammation, including leukocyte infiltration, inflammasome formation, and production of proinflammatory cytokines, following MI. Inhibition of MAFbx reduces mortality due to cardiac rupture after MI, in part through decreased MMP9 activity and leukocyte infiltration.
Author Disclosures: A. Chikata: None. S. Usui: None. S. Takashima: None. T. Kato: None. H. Murai: None. H. Furusho: None. S. Kaneko: None. J. Sadoshima: None. M. Takamura: None.
- © 2015 by American Heart Association, Inc.